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Sample records for activity relationship models

  1. Quantitative Structure Activity Relationship Models for the Antioxidant Activity of Polysaccharides

    PubMed Central

    Nie, Kaiying; Wang, Zhaojing

    2016-01-01

    In this study, quantitative structure activity relationship (QSAR) models for the antioxidant activity of polysaccharides were developed with 50% effective concentration (EC50) as the dependent variable. To establish optimum QSAR models, multiple linear regressions (MLR), support vector machines (SVM) and artificial neural networks (ANN) were used, and 11 molecular descriptors were selected. The optimum QSAR model for predicting EC50 of DPPH-scavenging activity consisted of four major descriptors. MLR model gave EC50 = 0.033Ara-0.041GalA-0.03GlcA-0.025PC+0.484, and MLR fitted the training set with R = 0.807. ANN model gave the improvement of training set (R = 0.96, RMSE = 0.018) and test set (R = 0.933, RMSE = 0.055) which indicated that it was more accurately than SVM and MLR models for predicting the DPPH-scavenging activity of polysaccharides. 67 compounds were used for predicting EC50 of the hydroxyl radicals scavenging activity of polysaccharides. MLR model gave EC50 = 0.12PC+0.083Fuc+0.013Rha-0.02UA+0.372. A comparison of results from models indicated that ANN model (R = 0.944, RMSE = 0.119) was also the best one for predicting the hydroxyl radicals scavenging activity of polysaccharides. MLR and ANN models showed that Ara and GalA appeared critical in determining EC50 of DPPH-scavenging activity, and Fuc, Rha, uronic acid and protein content had a great effect on the hydroxyl radicals scavenging activity of polysaccharides. The antioxidant activity of polysaccharide usually was high in MW range of 4000–100000, and the antioxidant activity could be affected simultaneously by other polysaccharide properties, such as uronic acid and Ara. PMID:27685320

  2. Quantitative Structure--Activity Relationship Modeling of Rat Acute Toxicity by Oral Exposure

    EPA Science Inventory

    Background: Few Quantitative Structure-Activity Relationship (QSAR) studies have successfully modeled large, diverse rodent toxicity endpoints. Objective: In this study, a combinatorial QSAR approach has been employed for the creation of robust and predictive models of acute toxi...

  3. Quantitative structure-activity relationship (QSAR) for insecticides: development of predictive in vivo insecticide activity models.

    PubMed

    Naik, P K; Singh, T; Singh, H

    2009-07-01

    Quantitative structure-activity relationship (QSAR) analyses were performed independently on data sets belonging to two groups of insecticides, namely the organophosphates and carbamates. Several types of descriptors including topological, spatial, thermodynamic, information content, lead likeness and E-state indices were used to derive quantitative relationships between insecticide activities and structural properties of chemicals. A systematic search approach based on missing value, zero value, simple correlation and multi-collinearity tests as well as the use of a genetic algorithm allowed the optimal selection of the descriptors used to generate the models. The QSAR models developed for both organophosphate and carbamate groups revealed good predictability with r(2) values of 0.949 and 0.838 as well as [image omitted] values of 0.890 and 0.765, respectively. In addition, a linear correlation was observed between the predicted and experimental LD(50) values for the test set data with r(2) of 0.871 and 0.788 for both the organophosphate and carbamate groups, indicating that the prediction accuracy of the QSAR models was acceptable. The models were also tested successfully from external validation criteria. QSAR models developed in this study should help further design of novel potent insecticides.

  4. A quantitative structure-activity relationship model for radical scavenging activity of flavonoids.

    PubMed

    Om, A; Kim, J H

    2008-03-01

    A quantitative structure-activity relationship (QSAR) study has been carried out for a training set of 29 flavonoids to correlate and predict the 1,1-diphenyl-2-picrylhydrazyl radical scavenging activity (RSA) values obtained from published data. Genetic algorithm and multiple linear regression were employed to select the descriptors and to generate the best prediction model that relates the structural features to the RSA activities using (1) three-dimensional (3D) Dragon (TALETE srl, Milan, Italy) descriptors and (2) semi-empirical descriptor calculations. The predictivity of the models was estimated by cross-validation with the leave-one-out method. The result showed that a significant improvement of the statistical indices was obtained by deleting outliers. Based on the data for the compounds used in this study, our results suggest a QSAR model of RSA that is based on the following descriptors: 3D-Morse, WHIM, and GETAWAY. Therefore, satisfactory relationships between RSA and the semi-empirical descriptors were found, demonstrating that the energy of the highest occupied molecular orbital, total energy, and energy of heat of formation contributed more significantly than all other descriptors.

  5. Antiproliferative Pt(IV) complexes: synthesis, biological activity, and quantitative structure-activity relationship modeling.

    PubMed

    Gramatica, Paola; Papa, Ester; Luini, Mara; Monti, Elena; Gariboldi, Marzia B; Ravera, Mauro; Gabano, Elisabetta; Gaviglio, Luca; Osella, Domenico

    2010-09-01

    Several Pt(IV) complexes of the general formula [Pt(L)2(L')2(L'')2] [axial ligands L are Cl-, RCOO-, or OH-; equatorial ligands L' are two am(m)ine or one diamine; and equatorial ligands L'' are Cl- or glycolato] were rationally designed and synthesized in the attempt to develop a predictive quantitative structure-activity relationship (QSAR) model. Numerous theoretical molecular descriptors were used alongside physicochemical data (i.e., reduction peak potential, Ep, and partition coefficient, log Po/w) to obtain a validated QSAR between in vitro cytotoxicity (half maximal inhibitory concentrations, IC50, on A2780 ovarian and HCT116 colon carcinoma cell lines) and some features of Pt(IV) complexes. In the resulting best models, a lipophilic descriptor (log Po/w or the number of secondary sp3 carbon atoms) plus an electronic descriptor (Ep, the number of oxygen atoms, or the topological polar surface area expressed as the N,O polar contribution) is necessary for modeling, supporting the general finding that the biological behavior of Pt(IV) complexes can be rationalized on the basis of their cellular uptake, the Pt(IV)-->Pt(II) reduction, and the structure of the corresponding Pt(II) metabolites. Novel compounds were synthesized on the basis of their predicted cytotoxicity in the preliminary QSAR model, and were experimentally tested. A final QSAR model, based solely on theoretical molecular descriptors to ensure its general applicability, is proposed.

  6. Validation of Quantitative Structure-Activity Relationship (QSAR) Model for Photosensitizer Activity Prediction

    PubMed Central

    Frimayanti, Neni; Yam, Mun Li; Lee, Hong Boon; Othman, Rozana; Zain, Sharifuddin M.; Rahman, Noorsaadah Abd.

    2011-01-01

    Photodynamic therapy is a relatively new treatment method for cancer which utilizes a combination of oxygen, a photosensitizer and light to generate reactive singlet oxygen that eradicates tumors via direct cell-killing, vasculature damage and engagement of the immune system. Most of photosensitizers that are in clinical and pre-clinical assessments, or those that are already approved for clinical use, are mainly based on cyclic tetrapyrroles. In an attempt to discover new effective photosensitizers, we report the use of the quantitative structure-activity relationship (QSAR) method to develop a model that could correlate the structural features of cyclic tetrapyrrole-based compounds with their photodynamic therapy (PDT) activity. In this study, a set of 36 porphyrin derivatives was used in the model development where 24 of these compounds were in the training set and the remaining 12 compounds were in the test set. The development of the QSAR model involved the use of the multiple linear regression analysis (MLRA) method. Based on the method, r2 value, r2 (CV) value and r2 prediction value of 0.87, 0.71 and 0.70 were obtained. The QSAR model was also employed to predict the experimental compounds in an external test set. This external test set comprises 20 porphyrin-based compounds with experimental IC50 values ranging from 0.39 μM to 7.04 μM. Thus the model showed good correlative and predictive ability, with a predictive correlation coefficient (r2 prediction for external test set) of 0.52. The developed QSAR model was used to discover some compounds as new lead photosensitizers from this external test set. PMID:22272096

  7. New Quantitative Structure-Activity Relationship Models Improve Predictability of Ames Mutagenicity for Aromatic Azo Compounds.

    PubMed

    Manganelli, Serena; Benfenati, Emilio; Manganaro, Alberto; Kulkarni, Sunil; Barton-Maclaren, Tara S; Honma, Masamitsu

    2016-10-01

    Existing Quantitative Structure-Activity Relationship (QSAR) models have limited predictive capabilities for aromatic azo compounds. In this study, 2 new models were built to predict Ames mutagenicity of this class of compounds. The first one made use of descriptors based on simplified molecular input-line entry system (SMILES), calculated with the CORAL software. The second model was based on the k-nearest neighbors algorithm. The statistical quality of the predictions from single models was satisfactory. The performance further improved when the predictions from these models were combined. The prediction results from other QSAR models for mutagenicity were also evaluated. Most of the existing models were found to be good at finding toxic compounds but resulted in many false positive predictions. The 2 new models specific for this class of compounds avoid this problem thanks to a larger set of related compounds as training set and improved algorithms.

  8. New Quantitative Structure-Activity Relationship Models Improve Predictability of Ames Mutagenicity for Aromatic Azo Compounds.

    PubMed

    Manganelli, Serena; Benfenati, Emilio; Manganaro, Alberto; Kulkarni, Sunil; Barton-Maclaren, Tara S; Honma, Masamitsu

    2016-10-01

    Existing Quantitative Structure-Activity Relationship (QSAR) models have limited predictive capabilities for aromatic azo compounds. In this study, 2 new models were built to predict Ames mutagenicity of this class of compounds. The first one made use of descriptors based on simplified molecular input-line entry system (SMILES), calculated with the CORAL software. The second model was based on the k-nearest neighbors algorithm. The statistical quality of the predictions from single models was satisfactory. The performance further improved when the predictions from these models were combined. The prediction results from other QSAR models for mutagenicity were also evaluated. Most of the existing models were found to be good at finding toxic compounds but resulted in many false positive predictions. The 2 new models specific for this class of compounds avoid this problem thanks to a larger set of related compounds as training set and improved algorithms. PMID:27413112

  9. Curating and Preparing High-Throughput Screening Data for Quantitative Structure-Activity Relationship Modeling.

    PubMed

    Kim, Marlene T; Wang, Wenyi; Sedykh, Alexander; Zhu, Hao

    2016-01-01

    Publicly available bioassay data often contains errors. Curating massive bioassay data, especially high-throughput screening (HTS) data, for Quantitative Structure-Activity Relationship (QSAR) modeling requires the assistance of automated data curation tools. Using automated data curation tools are beneficial to users, especially ones without prior computer skills, because many platforms have been developed and optimized based on standardized requirements. As a result, the users do not need to extensively configure the curation tool prior to the application procedure. In this chapter, a freely available automatic tool to curate and prepare HTS data for QSAR modeling purposes will be described.

  10. Curating and Preparing High-Throughput Screening Data for Quantitative Structure-Activity Relationship Modeling.

    PubMed

    Kim, Marlene T; Wang, Wenyi; Sedykh, Alexander; Zhu, Hao

    2016-01-01

    Publicly available bioassay data often contains errors. Curating massive bioassay data, especially high-throughput screening (HTS) data, for Quantitative Structure-Activity Relationship (QSAR) modeling requires the assistance of automated data curation tools. Using automated data curation tools are beneficial to users, especially ones without prior computer skills, because many platforms have been developed and optimized based on standardized requirements. As a result, the users do not need to extensively configure the curation tool prior to the application procedure. In this chapter, a freely available automatic tool to curate and prepare HTS data for QSAR modeling purposes will be described. PMID:27518634

  11. A Three-Dimensional Human Atrial Model with Fiber Orientation. Electrograms and Arrhythmic Activation Patterns Relationship

    PubMed Central

    Tobón, Catalina; Ruiz-Villa, Carlos A.; Heidenreich, Elvio; Romero, Lucia; Hornero, Fernando; Saiz, Javier

    2013-01-01

    The most common sustained cardiac arrhythmias in humans are atrial tachyarrhythmias, mainly atrial fibrillation. Areas of complex fractionated atrial electrograms and high dominant frequency have been proposed as critical regions for maintaining atrial fibrillation; however, there is a paucity of data on the relationship between the characteristics of electrograms and the propagation pattern underlying them. In this study, a realistic 3D computer model of the human atria has been developed to investigate this relationship. The model includes a realistic geometry with fiber orientation, anisotropic conductivity and electrophysiological heterogeneity. We simulated different tachyarrhythmic episodes applying both transient and continuous ectopic activity. Electrograms and their dominant frequency and organization index values were calculated over the entire atrial surface. Our simulations show electrograms with simple potentials, with little or no cycle length variations, narrow frequency peaks and high organization index values during stable and regular activity as the observed in atrial flutter, atrial tachycardia (except in areas of conduction block) and in areas closer to ectopic activity during focal atrial fibrillation. By contrast, cycle length variations and polymorphic electrograms with single, double and fragmented potentials were observed in areas of irregular and unstable activity during atrial fibrillation episodes. Our results also show: 1) electrograms with potentials without negative deflection related to spiral or curved wavefronts that pass over the recording point and move away, 2) potentials with a much greater proportion of positive deflection than negative in areas of wave collisions, 3) double potentials related with wave fragmentations or blocking lines and 4) fragmented electrograms associated with pivot points. Our model is the first human atrial model with realistic fiber orientation used to investigate the relationship between different

  12. Modeling structure-activity relationships of prodiginines with antimalarial activity using GA/MLR and OPS/PLS.

    PubMed

    de Campos, Luana Janaína; de Melo, Eduardo Borges

    2014-11-01

    In the present study, we performed a multivariate quantitative structure-activity relationship (QSAR) analysis of 52 prodiginines with antimalarial activity. Variable selection was based on the genetic algorithm (GA) and ordered predictor selection (OPS) approaches, and the models were built using the multiple linear regression (MLR) and partial least squares (PLS) regression methods. The leave-N-out crossvalidation and y-randomization tests showed that the models were robust and free from chance correlation. The mechanistic interpretation of the results was supported by earlier findings. In addition, the comparison of our models with those previously described indicated that the OPS/PLS-based model had a higher quality of external prediction. Thus, this study provides a comprehensive approach to the evaluation of the antimalarial activity of prodiginines, which may be used as a support tool in designing new therapeutic agents for malaria.

  13. Trainable structure-activity relationship model for virtual screening of CYP3A4 inhibition.

    PubMed

    Didziapetris, Remigijus; Dapkunas, Justas; Sazonovas, Andrius; Japertas, Pranas

    2010-11-01

    A new structure-activity relationship model predicting the probability for a compound to inhibit human cytochrome P450 3A4 has been developed using data for >800 compounds from various literature sources and tested on PubChem screening data. Novel GALAS (Global, Adjusted Locally According to Similarity) modeling methodology has been used, which is a combination of baseline global QSAR model and local similarity based corrections. GALAS modeling method allows forecasting the reliability of prediction thus defining the model applicability domain. For compounds within this domain the statistical results of the final model approach the data consistency between experimental data from literature and PubChem datasets with the overall accuracy of 89%. However, the original model is applicable only for less than a half of PubChem database. Since the similarity correction procedure of GALAS modeling method allows straightforward model training, the possibility to expand the applicability domain has been investigated. Experimental data from PubChem dataset served as an example of in-house high-throughput screening data. The model successfully adapted itself to both data classified using the same and different IC₅₀ threshold compared with the training set. In addition, adjustment of the CYP3A4 inhibition model to compounds with a novel chemical scaffold has been demonstrated. The reported GALAS model is proposed as a useful tool for virtual screening of compounds for possible drug-drug interactions even prior to the actual synthesis. PMID:20814717

  14. Quantitative structure-activity relationship models of chemical transformations from matched pairs analyses.

    PubMed

    Beck, Jeremy M; Springer, Clayton

    2014-04-28

    The concepts of activity cliffs and matched molecular pairs (MMP) are recent paradigms for analysis of data sets to identify structural changes that may be used to modify the potency of lead molecules in drug discovery projects. Analysis of MMPs was recently demonstrated as a feasible technique for quantitative structure-activity relationship (QSAR) modeling of prospective compounds. Although within a small data set, the lack of matched pairs, and the lack of knowledge about specific chemical transformations limit prospective applications. Here we present an alternative technique that determines pairwise descriptors for each matched pair and then uses a QSAR model to estimate the activity change associated with a chemical transformation. The descriptors effectively group similar transformations and incorporate information about the transformation and its local environment. Use of a transformation QSAR model allows one to estimate the activity change for novel transformations and therefore returns predictions for a larger fraction of test set compounds. Application of the proposed methodology to four public data sets results in increased model performance over a benchmark random forest and direct application of chemical transformations using QSAR-by-matched molecular pairs analysis (QSAR-by-MMPA).

  15. Isoxazole analogues bind the system xc- transporter: structure-activity relationship and pharmacophore model.

    PubMed

    Patel, Sarjubhai A; Rajale, Trideep; O'Brien, Erin; Burkhart, David J; Nelson, Jared K; Twamley, Brendan; Blumenfeld, Alex; Szabon-Watola, Monika I; Gerdes, John M; Bridges, Richard J; Natale, Nicholas R

    2010-01-01

    Analogues of amino methylisoxazole propionic acid (AMPA), were prepared from a common intermediate 12, including lipophilic analogues using lateral metalation and electrophilic quenching, and were evaluated at System xc-. Both the 5-naphthylethyl-(16) and 5-naphthylmethoxymethyl-(17) analogues adopt an E-conformation in the solid state, yet while the former has robust binding at System xc-, the latter is virtually devoid of activity. The most potent analogues were amino acid naphthyl-ACPA 7g, and hydrazone carboxylic acid, 11e Y=Y'=3,5-(CF(3))(2), which both inhibited glutamate uptake by the System xc- transporter with comparable potency to the endogenous substrate cystine, whereas in contrast the closed isoxazolo[3,4-d] pyridazinones 13 have significantly lower activity. A preliminary pharmacophore model has been constructed to provide insight into the analogue structure-activity relationships.

  16. Interpretable, probability-based confidence metric for continuous quantitative structure-activity relationship models.

    PubMed

    Keefer, Christopher E; Kauffman, Gregory W; Gupta, Rishi Raj

    2013-02-25

    A great deal of research has gone into the development of robust confidence in prediction and applicability domain (AD) measures for quantitative structure-activity relationship (QSAR) models in recent years. Much of the attention has historically focused on structural similarity, which can be defined in many forms and flavors. A concept that is frequently overlooked in the realm of the QSAR applicability domain is how the local activity landscape plays a role in how accurate a prediction is or is not. In this work, we describe an approach that pairs information about both the chemical similarity and activity landscape of a test compound's neighborhood into a single calculated confidence value. We also present an approach for converting this value into an interpretable confidence metric that has a simple and informative meaning across data sets. The approach will be introduced to the reader in the context of models built upon four diverse literature data sets. The steps we will outline include the definition of similarity used to determine nearest neighbors (NN), how we incorporate the NN activity landscape with a similarity-weighted root-mean-square distance (wRMSD) value, and how that value is then calibrated to generate an intuitive confidence metric for prospective application. Finally, we will illustrate the prospective performance of the approach on five proprietary models whose predictions and confidence metrics have been tracked for more than a year.

  17. Toxicity challenges in environmental chemicals: Prediction of human plasma protein binding through quantitative structure-activity relationship (QSAR) models

    EPA Science Inventory

    The present study explores the merit of utilizing available pharmaceutical data to construct a quantitative structure-activity relationship (QSAR) for prediction of the fraction of a chemical unbound to plasma protein (Fub) in environmentally relevant compounds. Independent model...

  18. Structure–Activity Relationships and Molecular Modeling of Sphingosine Kinase Inhibitors

    PubMed Central

    2013-01-01

    The design, synthesis, and evaluation of the potency of new isoform-selective inhibitors of sphingosine kinases 1 and 2 (SK1 and SK2), the enzyme that catalyzes the phosphorylation of d-erythro-sphingosine to produce the key signaling lipid, sphingosine 1-phosphate, are described. Recently, we reported that 1-(4-octylphenethyl)piperidin-4-ol (RB-005) is a selective inhibitor of SK1. Here we report the synthesis of 43 new analogues of RB-005, in which the lipophilic tail, polar headgroup, and linker region were modified to extend the structure–activity relationship profile for this lead compound, which we explain using modeling studies with the recently published crystal structure of SK1. We provide a basis for the key residues targeted by our profiled series and provide further evidence for the ability to discriminate between the two isoforms using pharmacological intervention. PMID:24164513

  19. Structure-activity relationships and molecular modeling of sphingosine kinase inhibitors.

    PubMed

    Baek, Dong Jae; MacRitchie, Neil; Anthony, Nahoum G; Mackay, Simon P; Pyne, Susan; Pyne, Nigel J; Bittman, Robert

    2013-11-27

    The design, synthesis, and evaluation of the potency of new isoform-selective inhibitors of sphingosine kinases 1 and 2 (SK1 and SK2), the enzyme that catalyzes the phosphorylation of d-erythro-sphingosine to produce the key signaling lipid, sphingosine 1-phosphate, are described. Recently, we reported that 1-(4-octylphenethyl)piperidin-4-ol (RB-005) is a selective inhibitor of SK1. Here we report the synthesis of 43 new analogues of RB-005, in which the lipophilic tail, polar headgroup, and linker region were modified to extend the structure-activity relationship profile for this lead compound, which we explain using modeling studies with the recently published crystal structure of SK1. We provide a basis for the key residues targeted by our profiled series and provide further evidence for the ability to discriminate between the two isoforms using pharmacological intervention.

  20. Developing sensor activity relationships for the JPL electronic nose sensors using molecular modeling and QSAR techniques

    NASA Technical Reports Server (NTRS)

    Shevade, A. V.; Ryan, M. A.; Homer, M. L.; Jewell, A. D.; Zhou, H.; Manatt, K.; Kisor, A. K.

    2005-01-01

    We report a Quantitative Structure-Activity Relationships (QSAR) study using Genetic Function Approximations (GFA) to describe the polymer-carbon composite sensor activities in the JPL Electronic Nose, when exposed to chemical vapors at parts-per-million concentration levels.

  1. Global quantitative structure-activity relationship models vs selected local models as predictors of off-target activities for project compounds.

    PubMed

    Sheridan, Robert P

    2014-04-28

    In the pharmaceutical industry, it is common for large numbers of compounds to be tested for off-target activities. Given a compound synthesized for an on-target project P, what is the best way to predict its off-target activity X? Is it better to use a global quantitative structure-activity relationship (QSAR) model calibrated against all compounds tested for X, or is it better to use a local model for X calibrated against only the set of compounds in project P? The literature is not consistent on this topic, and strong claims have been made for either. One particular idea is that local models will be superior to global models in prospective prediction if one generates many local models and chooses the type of local model that best predicts recent data. We tested this idea via simulated prospective prediction using in-house data involving compounds in 11 projects tested for 9 off-target activities. In our hands, the local model that best predicts the recent past is seldom the local model that is best at predicting the immediate future. Also, the local model that best predicts the recent past is not systematically better than the global model. This means the complexity of having project- or series-specific models for X can be avoided; a single global model for X is sufficient. We suggest that the relative predictivity of global vs local models may depend on the type of chemical descriptor used. Finally, we speculate why, contrary to observation, intuition suggests local models should be superior to global models.

  2. Quantitative structure-activity relationship modelling of oral acute toxicity and cytotoxic activity of fragrance materials in rodents.

    PubMed

    Papa, E; Luini, M; Gramatica, P

    2009-10-01

    Fragrance materials are used as ingredients in many consumer and personal care products. The wide and daily use of these substances, as well as their mainly uncontrolled discharge through domestic sewage, make fragrance materials both potential indoor and outdoor air pollutants which are also connected to possible toxic effects on humans (asthma, allergies, headaches). Unfortunately, little is known about the environmental fate and toxicity of these substances. However, the use of alternative, predictive approaches, such as quantitative structure-activity relationships (QSARs), can help in filling the data gap and in the characterization of the environmental and toxicological profile of these substances. In the proposed study, ordinary least squares regression-based QSAR models were developed for three toxicological endpoints: mouse oral LD(50), inhibition of NADH-oxidase (EC(50) NADH-Ox) and the effect on mitochondrial membrane potential (EC(50) DeltaPsim). Theoretical molecular descriptors were calculated by using DRAGON software, and the best QSAR models were developed according to the principles defined by the Organization for Economic Co-operation and Development.

  3. Longitudinal Relationships Between Productive Activities and Functional Health in Later Years: A Multivariate Latent Growth Curve Modeling Approach.

    PubMed

    Choi, Eunhee; Tang, Fengyan; Kim, Sung-Geun; Turk, Phillip

    2016-10-01

    This study examined the longitudinal relationships between functional health in later years and three types of productive activities: volunteering, full-time, and part-time work. Using the data from five waves (2000-2008) of the Health and Retirement Study, we applied multivariate latent growth curve modeling to examine the longitudinal relationships among individuals 50 or over. Functional health was measured by limitations in activities of daily living. Individuals who volunteered, worked either full time or part time exhibited a slower decline in functional health than nonparticipants. Significant associations were also found between initial functional health and longitudinal changes in productive activity participation. This study provides additional support for the benefits of productive activities later in life; engagement in volunteering and employment are indeed associated with better functional health in middle and old age. PMID:27461262

  4. Spaghetti Bridges: Modeling Linear Relationships

    ERIC Educational Resources Information Center

    Kroon, Cindy D.

    2016-01-01

    Mathematics and science are natural partners. One of many examples of this partnership occurs when scientific observations are made, thus providing data that can be used for mathematical modeling. Developing mathematical relationships elucidates such scientific principles. This activity describes a data-collection activity in which students employ…

  5. Quantitative structure-activity relationship modeling of polycyclic aromatic hydrocarbon mutagenicity by classification methods based on holistic theoretical molecular descriptors.

    PubMed

    Gramatica, Paola; Papa, Ester; Marrocchi, Assunta; Minuti, Lucio; Taticchi, Aldo

    2007-03-01

    Various polycyclic aromatic hydrocarbons (PAHs), ubiquitous environmental pollutants, are recognized mutagens and carcinogens. A homogeneous set of mutagenicity data (TA98 and TA100,+S9) for 32 benzocyclopentaphenanthrenes/chrysenes was modeled by the quantitative structure-activity relationship classification methods k-nearest neighbor and classification and regression tree, using theoretical holistic molecular descriptors. Genetic algorithm provided the selection of the best subset of variables for modeling mutagenicity. The models were validated by leave-one-out and leave-50%-out approaches and have good performance, with sensitivity and specificity ranges of 90-100%. Mutagenicity assessment for these PAHs requires only a few theoretical descriptors of their molecular structure.

  6. Improving quantitative structure-activity relationship models using Artificial Neural Networks trained with dropout.

    PubMed

    Mendenhall, Jeffrey; Meiler, Jens

    2016-02-01

    Dropout is an Artificial Neural Network (ANN) training technique that has been shown to improve ANN performance across canonical machine learning (ML) datasets. Quantitative Structure Activity Relationship (QSAR) datasets used to relate chemical structure to biological activity in Ligand-Based Computer-Aided Drug Discovery pose unique challenges for ML techniques, such as heavily biased dataset composition, and relatively large number of descriptors relative to the number of actives. To test the hypothesis that dropout also improves QSAR ANNs, we conduct a benchmark on nine large QSAR datasets. Use of dropout improved both enrichment false positive rate and log-scaled area under the receiver-operating characteristic curve (logAUC) by 22-46 % over conventional ANN implementations. Optimal dropout rates are found to be a function of the signal-to-noise ratio of the descriptor set, and relatively independent of the dataset. Dropout ANNs with 2D and 3D autocorrelation descriptors outperform conventional ANNs as well as optimized fingerprint similarity search methods.

  7. Novel Uses of In Vitro Data to Develop Quantitative Biological Activity Relationship Models for in Vivo Carcinogenicity Prediction.

    PubMed

    Pradeep, Prachi; Povinelli, Richard J; Merrill, Stephen J; Bozdag, Serdar; Sem, Daniel S

    2015-04-01

    The availability of large in vitro datasets enables better insight into the mode of action of chemicals and better identification of potential mechanism(s) of toxicity. Several studies have shown that not all in vitro assays can contribute as equal predictors of in vivo carcinogenicity for development of hybrid Quantitative Structure Activity Relationship (QSAR) models. We propose two novel approaches for the use of mechanistically relevant in vitro assay data in the identification of relevant biological descriptors and development of Quantitative Biological Activity Relationship (QBAR) models for carcinogenicity prediction. We demonstrate that in vitro assay data can be used to develop QBAR models for in vivo carcinogenicity prediction via two case studies corroborated with firm scientific rationale. The case studies demonstrate the similarities between QBAR and QSAR modeling in: (i) the selection of relevant descriptors to be used in the machine learning algorithm, and (ii) the development of a computational model that maps chemical or biological descriptors to a toxic endpoint. The results of both the case studies show: (i) improved accuracy and sensitivity which is especially desirable under regulatory requirements, and (ii) overall adherence with the OECD/REACH guidelines. Such mechanism based models can be used along with QSAR models for prediction of mechanistically complex toxic endpoints.

  8. Quantitative structure-activation barrier relationship modeling for Diels-Alder ligations utilizing quantum chemical structural descriptors

    PubMed Central

    2013-01-01

    Background In the present study, we show the correlation of quantum chemical structural descriptors with the activation barriers of the Diels-Alder ligations. A set of 72 non-catalysed Diels-Alder reactions were subjected to quantitative structure-activation barrier relationship (QSABR) under the framework of theoretical quantum chemical descriptors calculated solely from the structures of diene and dienophile reactants. Experimental activation barrier data were obtained from literature. Descriptors were computed using Hartree-Fock theory using 6-31G(d) basis set as implemented in Gaussian 09 software. Results Variable selection and model development were carried out by stepwise multiple linear regression methodology. Predictive performance of the quantitative structure-activation barrier relationship (QSABR) model was assessed by training and test set concept and by calculating leave-one-out cross-validated Q2 and predictive R2 values. The QSABR model can explain and predict 86.5% and 80% of the variances, respectively, in the activation energy barrier training data. Alternatively, a neural network model based on back propagation of errors was developed to assess the nonlinearity of the sought correlations between theoretical descriptors and experimental reaction barriers. Conclusions A reasonable predictability for the activation barrier of the test set reactions was obtained, which enabled an exploration and interpretation of the significant variables responsible for Diels-Alder interaction between dienes and dienophiles. Thus, studies in the direction of QSABR modelling that provide efficient and fast prediction of activation barriers of the Diels-Alder reactions turn out to be a meaningful alternative to transition state theory based computation. PMID:24171724

  9. Comparison between 5,10,15,20-tetraaryl- and 5,15-diarylporphyrins as photosensitizers: synthesis, photodynamic activity, and quantitative structure-activity relationship modeling.

    PubMed

    Banfi, Stefano; Caruso, Enrico; Buccafurni, Loredana; Murano, Roberto; Monti, Elena; Gariboldi, Marzia; Papa, Ester; Gramatica, Paola

    2006-06-01

    The synthesis of a panel of seven nonsymmetric 5,10,15,20-tetraarylporphyrins, 13 symmetric and nonsymmetric 5,15-diarylporphyrins, and one 5,15-diarylchlorin is described. In vitro photodynamic activities on HCT116 human colon adenocarcinoma cells were evaluated by standard cytotoxicity assays. A predictive quantitative structure-activity relationship (QSAR) regression model, based on theoretical holistic molecular descriptors, of a series of 34 tetrapyrrolic photosensitizers (PSs), including the 24 compounds synthesized in this work, was developed to describe the relationship between structural features and photodynamic activity. The present study demonstrates that structural features significantly influence the photodynamic activity of tetrapyrrolic derivatives: diaryl compounds were more active with respect to the tetraarylporphyrins, and among the diaryl derivatives, hydroxy-substituted compounds were more effective than the corresponding methoxy-substituted ones. Furthermore, three monoarylporphyrins, isolated as byproducts during diarylporphyrin synthesis, were considered for both photodynamic and QSAR studies; surprisingly they were found to be particularly active photosensitizers.

  10. Molecular modeling and snake venom phospholipase A2 inhibition by phenolic compounds: Structure-activity relationship.

    PubMed

    Alam, Md Iqbal; Alam, Mohammed A; Alam, Ozair; Nargotra, Amit; Taneja, Subhash Chandra; Koul, Surrinder

    2016-05-23

    In our earlier study, we have reported that a phenolic compound 2-hydroxy-4-methoxybenzaldehyde from Janakia arayalpatra root extract was active against Viper and Cobra envenomations. Based on the structure of this natural product, libraries of synthetic structurally variant phenolic compounds were studied through molecular docking on the venom protein. To validate the activity of eight selected compounds, we have tested them in in vivo and in vitro models. The compound 21 (2-hydroxy-3-methoxy benzaldehyde), 22 (2-hydroxy-4-methoxybenzaldehyde) and 35 (2-hydroxy-3-methoxybenzylalcohol) were found to be active against venom-induced pathophysiological changes. The compounds 20, 15 and 35 displayed maximum anti-hemorrhagic, anti-lethal and PLA2 inhibitory activity respectively. In terms of SAR, the presence of a formyl group in conjunction with a phenolic group was seen as a significant contributor towards increasing the antivenom activity. The above observations confirmed the anti-venom activity of the phenolic compounds which needs to be further investigated for the development of new anti-snake venom leads. PMID:26986086

  11. Modeling chemical interaction profiles: I. Spectral data-activity relationship and structure-activity relationship models for inhibitors and non-inhibitors of cytochrome P450 CYP3A4 and CYP2D6 isozymes.

    PubMed

    McPhail, Brooks; Tie, Yunfeng; Hong, Huixiao; Pearce, Bruce A; Schnackenberg, Laura K; Ge, Weigong; Valerio, Luis G; Fuscoe, James C; Tong, Weida; Buzatu, Dan A; Wilkes, Jon G; Fowler, Bruce A; Demchuk, Eugene; Beger, Richard D

    2012-03-15

    An interagency collaboration was established to model chemical interactions that may cause adverse health effects when an exposure to a mixture of chemicals occurs. Many of these chemicals--drugs, pesticides, and environmental pollutants--interact at the level of metabolic biotransformations mediated by cytochrome P450 (CYP) enzymes. In the present work, spectral data-activity relationship (SDAR) and structure-activity relationship (SAR) approaches were used to develop machine-learning classifiers of inhibitors and non-inhibitors of the CYP3A4 and CYP2D6 isozymes. The models were built upon 602 reference pharmaceutical compounds whose interactions have been deduced from clinical data, and 100 additional chemicals that were used to evaluate model performance in an external validation (EV) test. SDAR is an innovative modeling approach that relies on discriminant analysis applied to binned nuclear magnetic resonance (NMR) spectral descriptors. In the present work, both 1D ¹³C and 1D ¹⁵N-NMR spectra were used together in a novel implementation of the SDAR technique. It was found that increasing the binning size of 1D ¹³C-NMR and ¹⁵N-NMR spectra caused an increase in the tenfold cross-validation (CV) performance in terms of both the rate of correct classification and sensitivity. The results of SDAR modeling were verified using SAR. For SAR modeling, a decision forest approach involving from 6 to 17 Mold2 descriptors in a tree was used. Average rates of correct classification of SDAR and SAR models in a hundred CV tests were 60% and 61% for CYP3A4, and 62% and 70% for CYP2D6, respectively. The rates of correct classification of SDAR and SAR models in the EV test were 73% and 86% for CYP3A4, and 76% and 90% for CYP2D6, respectively. Thus, both SDAR and SAR methods demonstrated a comparable performance in modeling a large set of structurally diverse data. Based on unique NMR structural descriptors, the new SDAR modeling method complements the existing SAR

  12. Modeling the relationship between photosynthetically active radiation and global horizontal irradiance using singular spectrum analysis

    NASA Astrophysics Data System (ADS)

    Zempila, Melina-Maria; Taylor, Michael; Bais, Alkiviadis; Kazadzis, Stelios

    2016-10-01

    We report on the construction of generic models to calculate photosynthetically active radiation (PAR) from global horizontal irradiance (GHI), and vice versa. Our study took place at stations of the Greek UV network (UVNET) and the Hellenic solar energy network (HNSE) with measurements from NILU-UV multi-filter radiometers and CM pyranometers, chosen due to their long (≈1 M record/site) high temporal resolution (≈1 min) record that captures a broad range of atmospheric environments and cloudiness conditions. The uncertainty of the PAR measurements is quantified to be ±6.5% while the uncertainty involved in GHI measurements is up to ≈±7% according to the manufacturer. We show how multi-linear regression and nonlinear neural network (NN) models, trained at a calibration site (Thessaloniki) can be made generic provided that the input-output time series are processed with multi-channel singular spectrum analysis (M-SSA). Without M-SSA, both linear and nonlinear models perform well only locally. M-SSA with 50 time-lags is found to be sufficient for identification of trend, periodic and noise components in aerosol, cloud parameters and irradiance, and to construct regularized noise models of PAR from GHI irradiances. Reconstructed PAR and GHI time series capture ≈95% of the variance of the cross-validated target measurements and have median absolute percentage errors <2%. The intra-site median absolute error of M-SSA processed models were ≈8.2±1.7 W/m2 for PAR and ≈9.2±4.2 W/m2 for GHI. When applying the models trained at Thessaloniki to other stations, the average absolute mean bias between the model estimates and measured values was found to be ≈1.2 W/m2 for PAR and ≈0.8 W/m2 for GHI. For the models, percentage errors are well within the uncertainty of the measurements at all sites. Generic NN models were found to perform marginally better than their linear counterparts.

  13. Modeling liver-related adverse effects of drugs using knearest neighbor quantitative structure-activity relationship method.

    PubMed

    Rodgers, Amie D; Zhu, Hao; Fourches, Denis; Rusyn, Ivan; Tropsha, Alexander

    2010-04-19

    Adverse effects of drugs (AEDs) continue to be a major cause of drug withdrawals in both development and postmarketing. While liver-related AEDs are a major concern for drug safety, there are few in silico models for predicting human liver toxicity for drug candidates. We have applied the quantitative structure-activity relationship (QSAR) approach to model liver AEDs. In this study, we aimed to construct a QSAR model capable of binary classification (active vs inactive) of drugs for liver AEDs based on chemical structure. To build QSAR models, we have employed an FDA spontaneous reporting database of human liver AEDs (elevations in activity of serum liver enzymes), which contains data on approximately 500 approved drugs. Approximately 200 compounds with wide clinical data coverage, structural similarity, and balanced (40/60) active/inactive ratios were selected for modeling and divided into multiple training/test and external validation sets. QSAR models were developed using the k nearest neighbor method and validated using external data sets. Models with high sensitivity (>73%) and specificity (>94%) for the prediction of liver AEDs in external validation sets were developed. To test applicability of the models, three chemical databases (World Drug Index, Prestwick Chemical Library, and Biowisdom Liver Intelligence Module) were screened in silico, and the validity of predictions was determined, where possible, by comparing model-based classification with assertions in publicly available literature. Validated QSAR models of liver AEDs based on the data from the FDA spontaneous reporting system can be employed as sensitive and specific predictors of AEDs in preclinical screening of drug candidates for potential hepatotoxicity in humans. PMID:20192250

  14. Using quantitative structure-activity relationship modeling to quantitatively predict the developmental toxicity of halogenated azole compounds.

    PubMed

    Craig, Evisabel A; Wang, Nina Ching; Zhao, Q Jay

    2014-07-01

    Developmental toxicity is a relevant endpoint for the comprehensive assessment of human health risk from chemical exposure. However, animal developmental toxicity data remain unavailable for many environmental contaminants due to the complexity and cost of these types of analyses. Here we describe an approach that uses quantitative structure-activity relationship modeling as an alternative methodology to fill data gaps in the developmental toxicity profile of certain halogenated compounds. Chemical information was obtained and curated using the OECD Quantitative Structure-Activity Relationship Toolbox, version 3.0. Data from 35 curated compounds were analyzed via linear regression to build the predictive model, which has an R(2) of 0.79 and a Q(2) of 0.77. The applicability domain (AD) was defined by chemical category and structural similarity. Seven halogenated chemicals that fit the AD but are not part of the training set were employed for external validation purposes. Our model predicted lowest observed adverse effect level values with a maximal threefold deviation from the observed experimental values for all chemicals that fit the AD. The good predictability of our model suggests that this method may be applicable to the analysis of qualifying compounds whenever developmental toxicity information is lacking or incomplete for risk assessment considerations.

  15. Development of quantitative structure activity relationship (QSAR) model for disinfection byproduct (DBP) research: A review of methods and resources.

    PubMed

    Chen, Baiyang; Zhang, Tian; Bond, Tom; Gan, Yiqun

    2015-12-15

    Quantitative structure-activity relationship (QSAR) models are tools for linking chemical activities with molecular structures and compositions. Due to the concern about the proliferating number of disinfection byproducts (DBPs) in water and the associated financial and technical burden, researchers have recently begun to develop QSAR models to investigate the toxicity, formation, property, and removal of DBPs. However, there are no standard procedures or best practices regarding how to develop QSAR models, which potentially limit their wide acceptance. In order to facilitate more frequent use of QSAR models in future DBP research, this article reviews the processes required for QSAR model development, summarizes recent trends in QSAR-DBP studies, and shares some important resources for QSAR development (e.g., free databases and QSAR programs). The paper follows the four steps of QSAR model development, i.e., data collection, descriptor filtration, algorithm selection, and model validation; and finishes by highlighting several research needs. Because QSAR models may have an important role in progressing our understanding of DBP issues, it is hoped that this paper will encourage their future use for this application.

  16. Quantitative structure-activity relationship modeling on in vitro endocrine effects and metabolic stability involving 26 selected brominated flame retardants.

    PubMed

    Harju, Mikael; Hamers, Timo; Kamstra, Jorke H; Sonneveld, Edwin; Boon, Jan P; Tysklind, Mats; Andersson, Patrik L

    2007-04-01

    In this work, quantitative structure-activity relationships (QSARs) were developed to aid human and environmental risk assessment processes for brominated flame retardants (BFRs). Brominated flame retardants, such as the high-production-volume chemicals polybrominated diphenyl ethers (PBDEs), tetrabromobisphenol A, and hexabromocyclododecane, have been identified as potential endocrine disruptors. Quantitative structure-activity relationship models were built based on the in vitro potencies of 26 selected BFRs. The in vitro assays included interactions with, for example, androgen, progesterone, estrogen, and dioxin (aryl hydrocarbon) receptor, plus competition with thyroxine for its plasma carrier protein (transthyretin), inhibition of estradiol sulfation via sulfotransferase, and finally, rate of metabolization. The QSAR modeling, a number of physicochemical parameters were calculated describing the electronic, lipophilic, and structural characteristics of the molecules. These include frontier molecular orbitals, molecular charges, polarities, log octanol/water partitioning coefficient, and two- and three-dimensional molecularproperties. Experimental properties were included and measured for PBDEs, such as their individual ultraviolet spectra (200-320 nm) and retention times on three different high-performance liquid chromatography columns and one nonpolar gas chromatography column. Quantitative structure-activity relationship models based on androgen antagonism and metabolic degradation rates generally gave similar results, suggesting that lower-brominated PBDEs with bromine substitutions in ortho positions and bromine-free meta- and para positions had the highest potencies and metabolic degradation rates. Predictions made for the constituents of the technical flame retardant Bromkal 70-5DE found BDE 17 to be a potent androgen antagonist and BDE 66, which is a relevant PBDE in environmental samples, to be only a weak antagonist.

  17. Structure activity relationship modelling of milk protein-derived peptides with dipeptidyl peptidase IV (DPP-IV) inhibitory activity.

    PubMed

    Nongonierma, Alice B; FitzGerald, Richard J

    2016-05-01

    Quantitative structure activity type models were developed in an attempt to predict the key features of peptide sequences having dipeptidyl peptidase IV (DPP-IV) inhibitory activity. The models were then employed to help predict the potential of peptides, which are currently reported in the literature to be present in the intestinal tract of humans following milk/dairy product ingestion, to act as inhibitors of DPP-IV. Two models (z- and v-scale) for short (2-5 amino acid residues) bovine milk peptides, behaving as competitive inhibitors of DPP-IV, were developed. The z- and the v-scale models (p<0.05, R(2) of 0.829 and 0.815, respectively) were then applied to 56 milk protein-derived peptides previously reported in the literature to be found in the intestinal tract of humans which possessed a structural feature of DPP-IV inhibitory peptides (P at the N2 position). Ten of these peptides were synthetized and tested for their in vitro DPP-IV inhibitory properties. There was no agreement between the predicted and experimentally determined DPP-IV half maximal inhibitory concentrations (IC50) for the competitive peptide inhibitors. However, the ranking for DPP-IV inhibitory potency of the competitive peptide inhibitors was conserved. Furthermore, potent in vitro DPP-IV inhibitory activity was observed with two peptides, LPVPQ (IC50=43.8±8.8μM) and IPM (IC50=69.5±8.7μM). Peptides present within the gastrointestinal tract of human may have promise for the development of natural DPP-IV inhibitors for the management of serum glucose.

  18. Structural similarity based kriging for quantitative structure activity and property relationship modeling.

    PubMed

    Teixeira, Ana L; Falcao, Andre O

    2014-07-28

    Structurally similar molecules tend to have similar properties, i.e. closer molecules in the molecular space are more likely to yield similar property values while distant molecules are more likely to yield different values. Based on this principle, we propose the use of a new method that takes into account the high dimensionality of the molecular space, predicting chemical, physical, or biological properties based on the most similar compounds with measured properties. This methodology uses ordinary kriging coupled with three different molecular similarity approaches (based on molecular descriptors, fingerprints, and atom matching) which creates an interpolation map over the molecular space that is capable of predicting properties/activities for diverse chemical data sets. The proposed method was tested in two data sets of diverse chemical compounds collected from the literature and preprocessed. One of the data sets contained dihydrofolate reductase inhibition activity data, and the second molecules for which aqueous solubility was known. The overall predictive results using kriging for both data sets comply with the results obtained in the literature using typical QSPR/QSAR approaches. However, the procedure did not involve any type of descriptor selection or even minimal information about each problem, suggesting that this approach is directly applicable to a large spectrum of problems in QSAR/QSPR. Furthermore, the predictive results improve significantly with the similarity threshold between the training and testing compounds, allowing the definition of a confidence threshold of similarity and error estimation for each case inferred. The use of kriging for interpolation over the molecular metric space is independent of the training data set size, and no reparametrizations are necessary when more compounds are added or removed from the set, and increasing the size of the database will consequentially improve the quality of the estimations. Finally it is shown

  19. Qualitative and quantitative structure-activity relationship modelling for predicting blood-brain barrier permeability of structurally diverse chemicals.

    PubMed

    Gupta, S; Basant, N; Singh, K P

    2015-01-01

    In this study, structure-activity relationship (SAR) models have been established for qualitative and quantitative prediction of the blood-brain barrier (BBB) permeability of chemicals. The structural diversity of the chemicals and nonlinear structure in the data were tested. The predictive and generalization ability of the developed SAR models were tested through internal and external validation procedures. In complete data, the QSAR models rendered ternary classification accuracy of >98.15%, while the quantitative SAR models yielded correlation (r(2)) of >0.926 between the measured and the predicted BBB permeability values with the mean squared error (MSE) <0.045. The proposed models were also applied to an external new in vitro data and yielded classification accuracy of >82.7% and r(2) > 0.905 (MSE < 0.019). The sensitivity analysis revealed that topological polar surface area (TPSA) has the highest effect in qualitative and quantitative models for predicting the BBB permeability of chemicals. Moreover, these models showed predictive performance superior to those reported earlier in the literature. This demonstrates the appropriateness of the developed SAR models to reliably predict the BBB permeability of new chemicals, which can be used for initial screening of the molecules in the drug development process.

  20. Peptide inhibitors of botulinum neurotoxin serotype A: design, inhibition, cocrystal structures, structure-activity relationship and pharmacophore modeling

    SciTech Connect

    Kumar G.; Swaminathan S.; Kumaran, D.; Ahmed, S. A.

    2012-05-01

    Clostridium botulinum neurotoxins are classified as Category A bioterrorism agents by the Centers for Disease Control and Prevention (CDC). The seven serotypes (A-G) of the botulinum neurotoxin, the causative agent of the disease botulism, block neurotransmitter release by specifically cleaving one of the three SNARE (soluble N-ethylmaleimide-sensitive factor attachment protein receptor) proteins and induce flaccid paralysis. Using a structure-based drug-design approach, a number of peptide inhibitors were designed and their inhibitory activity against botulinum serotype A (BoNT/A) protease was determined. The most potent peptide, RRGF, inhibited BoNT/A protease with an IC{sub 50} of 0.9 {micro}M and a K{sub i} of 358 nM. High-resolution crystal structures of various peptide inhibitors in complex with the BoNT/A protease domain were also determined. Based on the inhibitory activities and the atomic interactions deduced from the cocrystal structures, the structure-activity relationship was analyzed and a pharmacophore model was developed. Unlike the currently available models, this pharmacophore model is based on a number of enzyme-inhibitor peptide cocrystal structures and improved the existing models significantly, incorporating new features.

  1. Assessment of quantitative structure-activity relationship of toxicity prediction models for Korean chemical substance control legislation

    PubMed Central

    Kim, Kwang-Yon; Shin, Seong Eun; No, Kyoung Tai

    2015-01-01

    Objectives For successful adoption of legislation controlling registration and assessment of chemical substances, it is important to obtain sufficient toxicological experimental evidence and other related information. It is also essential to obtain a sufficient number of predicted risk and toxicity results. Particularly, methods used in predicting toxicities of chemical substances during acquisition of required data, ultimately become an economic method for future dealings with new substances. Although the need for such methods is gradually increasing, the-required information about reliability and applicability range has not been systematically provided. Methods There are various representative environmental and human toxicity models based on quantitative structure-activity relationships (QSAR). Here, we secured the 10 representative QSAR-based prediction models and its information that can make predictions about substances that are expected to be regulated. We used models that predict and confirm usability of the information expected to be collected and submitted according to the legislation. After collecting and evaluating each predictive model and relevant data, we prepared methods quantifying the scientific validity and reliability, which are essential conditions for using predictive models. Results We calculated predicted values for the models. Furthermore, we deduced and compared adequacies of the models using the Alternative non-testing method assessed for Registration, Evaluation, Authorization, and Restriction of Chemicals Substances scoring system, and deduced the applicability domains for each model. Additionally, we calculated and compared inclusion rates of substances expected to be regulated, to confirm the applicability. Conclusions We evaluated and compared the data, adequacy, and applicability of our selected QSAR-based toxicity prediction models, and included them in a database. Based on this data, we aimed to construct a system that can be used

  2. Synthetic cannabinoids: In silico prediction of the cannabinoid receptor 1 affinity by a quantitative structure-activity relationship model.

    PubMed

    Paulke, Alexander; Proschak, Ewgenij; Sommer, Kai; Achenbach, Janosch; Wunder, Cora; Toennes, Stefan W

    2016-03-14

    The number of new synthetic psychoactive compounds increase steadily. Among the group of these psychoactive compounds, the synthetic cannabinoids (SCBs) are most popular and serve as a substitute of herbal cannabis. More than 600 of these substances already exist. For some SCBs the in vitro cannabinoid receptor 1 (CB1) affinity is known, but for the majority it is unknown. A quantitative structure-activity relationship (QSAR) model was developed, which allows the determination of the SCBs affinity to CB1 (expressed as binding constant (Ki)) without reference substances. The chemically advance template search descriptor was used for vector representation of the compound structures. The similarity between two molecules was calculated using the Feature-Pair Distribution Similarity. The Ki values were calculated using the Inverse Distance Weighting method. The prediction model was validated using a cross validation procedure. The predicted Ki values of some new SCBs were in a range between 20 (considerably higher affinity to CB1 than THC) to 468 (considerably lower affinity to CB1 than THC). The present QSAR model can serve as a simple, fast and cheap tool to get a first hint of the biological activity of new synthetic cannabinoids or of other new psychoactive compounds.

  3. Modeling chemical interaction profiles: II. Molecular docking, spectral data-activity relationship, and structure-activity relationship models for potent and weak inhibitors of cytochrome P450 CYP3A4 isozyme.

    PubMed

    Tie, Yunfeng; McPhail, Brooks; Hong, Huixiao; Pearce, Bruce A; Schnackenberg, Laura K; Ge, Weigong; Buzatu, Dan A; Wilkes, Jon G; Fuscoe, James C; Tong, Weida; Fowler, Bruce A; Beger, Richard D; Demchuk, Eugene

    2012-03-15

    Polypharmacy increasingly has become a topic of public health concern, particularly as the U.S. population ages. Drug labels often contain insufficient information to enable the clinician to safely use multiple drugs. Because many of the drugs are bio-transformed by cytochrome P450 (CYP) enzymes, inhibition of CYP activity has long been associated with potentially adverse health effects. In an attempt to reduce the uncertainty pertaining to CYP-mediated drug-drug/chemical interactions, an interagency collaborative group developed a consensus approach to prioritizing information concerning CYP inhibition. The consensus involved computational molecular docking, spectral data-activity relationship (SDAR), and structure-activity relationship (SAR) models that addressed the clinical potency of CYP inhibition. The models were built upon chemicals that were categorized as either potent or weak inhibitors of the CYP3A4 isozyme. The categorization was carried out using information from clinical trials because currently available in vitro high-throughput screening data were not fully representative of the in vivo potency of inhibition. During categorization it was found that compounds, which break the Lipinski rule of five by molecular weight, were about twice more likely to be inhibitors of CYP3A4 compared to those, which obey the rule. Similarly, among inhibitors that break the rule, potent inhibitors were 2-3 times more frequent. The molecular docking classification relied on logistic regression, by which the docking scores from different docking algorithms, CYP3A4 three-dimensional structures, and binding sites on them were combined in a unified probabilistic model. The SDAR models employed a multiple linear regression approach applied to binned 1D ¹³C-NMR and 1D ¹⁵N-NMR spectral descriptors. Structure-based and physical-chemical descriptors were used as the basis for developing SAR models by the decision forest method. Thirty-three potent inhibitors and 88 weak

  4. Quantitative structure-activity relationship models that stand the test of time.

    PubMed

    Davis, Andrew M; Wood, David J

    2013-04-01

    The pharmaceutical industry is in a period of intense change. While this has many drivers, attrition through the development process continues to be an important pressure. The emerging definitions of "compound quality" that are based on retrospective analyses of developmental attrition have highlighted a new direction for medicinal chemistry and the paradigm of "quality at the point of design". The time has come for retrospective analyses to catalyze prospective action. Quality at the point of design places pressure on the quality of our predictive models. Empirical QSAR models when built with care provide true predictive control, but their accuracy and precision can be improved. Here we describe AstraZeneca's experience of automation in QSAR model building and validation, and how an informatics system can provide a step-change in predictive power to project design teams, if they choose to use it.

  5. The ISO Edi Conceptual Model Activity and Its Relationship to OSI.

    ERIC Educational Resources Information Center

    Fincher, Judith A.

    1990-01-01

    The edi conceptual model is being developed to define common structures, services, and processes that syntax-specific standards like X12 and EDIFACT could adopt. Open Systems Interconnection (OSI) is of interest to edi because of its potential to help enable global interoperability across Electronic Data Interchange (EDI) functional groups. A…

  6. Active and passive characteristics of muscle tone and their relationship to models of subluxation/joint dysfunction

    PubMed Central

    Knutson, Gary A; Owens, Edward F

    2003-01-01

    The relationship of muscles to the causes and effects of the pathophysiologic entity referred to as chiropractic subluxation or joint dysfunction is critical. Part I of this paper reviews complexities of skeletal muscle in regards to anatomy, active and passive tone, detection of muscle tone, neurophysiology, and how muscle function fits into a variety of subluxation/joint dysfunction models. The review culminates in Part II with a hypothesis to describe and explain varying degrees of muscle tone that may be encountered clinically. It is hoped that knowledge of the differing levels of muscle tone and their causes will help the clinician to better determine the underlying cause of a neuro-musculoskeletal problem allowing application of necessary and proper intervention. Imagesp179-a

  7. Active and passive characteristics of muscle tone and their relationship to models of subluxation/joint dysfunction

    PubMed Central

    Knutson, Gary A.; Owens, Edward F.

    2003-01-01

    The relationship of muscles to the causes and effects of the pathophysiologic entity referred to as chiropractic subluxation or joint dysfunction is critical. Part I of this paper reviewed the complexities of skeletal muscle in regards to anatomy, active and passive tone, detection of muscle tone, neurophysiology, and how muscle function fits into a variety of subluxation/joint dysfunction models. The concluding part of the review culminates in a hypothesis to describe and explain varying degrees of muscle tone that may be encountered clinically. It is hoped that knowledge of the differing levels of muscle tone and their causes will help the clinician to better determine the underlying cause of a neuromusculoskeletal problem allowing application of necessary and proper intervention.

  8. The relationship between school physical activity policy and objectively measured physical activity of elementary school students: a multilevel model analysis

    PubMed Central

    2014-01-01

    Background There is evidence of school level variability in the physical activity of children and youth. Less is known about factors that may contribute to this variation. The purpose of this study was to examine if the school health environment (Healthy Physical Environment, Instruction and Programs, Supportive Social Environment, and Community Partnerships) is associated with objectively measured time spent in light to vigorous physical activity among a sample of Toronto children. Methods The sample comprised 856 grade 5 and 6 students from 18 elementary schools in Toronto, Ontario. Multilevel linear regression analyses were used to examine the impact of school physical activity policy on students’ time spent in light-to-vigorous physical activity. Results Significant between-school random variation in objectively measured time spent in light-to-vigorous physical activity was identified [σ2μ0 = 0.067; p < 0.001]; school-level differences accounted for 6.7% of the variability in the time individual students spent in light-to-vigorous physical activity. Of the 22 school-level variables, students attending schools with support for active transportation to/from school and written policies/practices for physical activity, accumulated significantly more minutes of physical activity per school week than students who attended schools that did not. Conclusions School physical activity policy and support for active school travel is associated with objectively measured time spent in light to vigorous physical activity. School physical activity policy might be a critical mechanism through which schools can impact the physical activity levels of their students. PMID:24999387

  9. A novel quantitative structure-activity relationship model for prediction of biomagnification factor of some organochlorine pollutants.

    PubMed

    Fatemi, Mohammad Hossein; Baher, Elham

    2009-08-01

    The biomagnification factor (BMF) is an important property for toxicology and environmental chemistry. In this work, quantitative structure-activity relationship (QSAR) models were used for the prediction of BMF for a data set including 30 polychlorinated biphenyls and 12 organochlorine pollutants. This set was divided into training and prediction sets. The result of diversity test reveals that the structure of the training and test sets can represent those of the whole ones. After calculation and screening of a large number of molecular descriptors, the methods of stepwise multiple linear regression and genetic algorithm (GA) were used for the selection of most important and significant descriptors which were related to BMF. Then multiple linear regression and artificial neural network (ANN) techniques were applied as linear and non-linear feature mapping techniques, respectively. By comparison between statistical parameters of these methods it was concluded that an ANN model, which used GA selected descriptors, was superior over constructed models. Descriptors which were used by this model are: topographic electronic index, complementary information content, XY shadow/XY rectangle and difference between partial positively and negatively charge surface area. The standard errors for training and test sets of this model are 0.03 and 0.20, respectively. The degree of importance of each descriptor was evaluated by sensitivity analysis approach for the nonlinear model. A good results (Q (2) = 0.97 and SPRESS = 0.084) is obtained by applying cross-validation test that indicating the validation of descriptors in the obtained model in prediction of BMF for these compounds. PMID:19219557

  10. Applying quantitative structure-activity relationship (QSAR) methodology for modeling postmortem redistribution of benzodiazepines and tricyclic antidepressants.

    PubMed

    Giaginis, Constantinos; Tsantili-Kakoulidou, Anna; Theocharis, Stamatios

    2014-06-01

    Postmortem redistribution (PMR) constitutes a multifaceted process, which complicates the interpretation of drug concentrations by forensic toxicologists. The present study aimed to apply quantitative structure-activity relationship (QSAR) analysis for modeling PMR data of structurally related drugs, 10 benzodiazepines and 10 tricyclic antidepressants. For benzodiazepines, an adequate QSAR model was obtained (R(2) = 0.98, Q(2) = 0.88, RMSEE = 0.12), in which energy, ionization and molecular size exerted significant impact. For tricyclic antidepressants, an adequate QSAR model with slightly inferior statistics (R(2) = 0.95, Q(2) = 0.87, RMSEE = 0.29) was established after exclusion of maprotiline, in which energy parameters, basicity character and lipophilicity exerted significant contribution. Thus, QSAR analysis could be used as a complementary tool to provide an informative illustration of the contributing molecular, physicochemical and structural properties in PMR process. However, the complexity, non-static and time-dependent nature of PMR endpoints raises serious concerns whether QSAR methodology could predict the degree of redistribution, highlighting the need for animal-derived PMR data.

  11. Quantitative structure-activity relationship model for the fetal-maternal blood concentration ratio of chemicals in humans.

    PubMed

    Takaku, Tomoyuki; Nagahori, Hirohisa; Sogame, Yoshihisa; Takagi, Tatsuya

    2015-01-01

    A quantitative structure-activity relationship (QSAR) model of the fetal-maternal blood concentration ratio (F/M ratio) of chemicals was developed to predict the placental transfer in humans. Data on F/M ratio of 55 compounds found in the literature were separated into training (75%, 41 compounds) and testing sets (25%, 14 compounds). The training sets were then subjected to multiple linear regression analysis using the descriptors of molecular weight (MW), topological polar surface area (TopoPSA), and maximum E-state of hydrogen atom (Hmax). Multiple linear regression analysis and a cross-validation showed a relatively high adjusted coefficient of determination (Ra(2)) (0.73) and cross-validated coefficient of determination (Q(2)) (0.71), after removing three outliers. In the external validation, R(2) for external validation (R(2)pred) was calculated to be 0.51. These results suggested that the QSAR model developed in this study can be considered reliable in terms of its robustness and predictive performance. Since it is difficult to examine the F/M ratio in humans experimentally, this QSAR model for prediction of the placental transfer of chemicals in humans could be useful in risk assessment of chemicals in humans.

  12. Benzimidazole-Based Quinazolines: In Vitro Evaluation, Quantitative Structure-Activity Relationship, and Molecular Modeling as Aurora Kinase Inhibitors.

    PubMed

    Sharma, Alka; Luxami, Vijay; Saxena, Sanjai; Paul, Kamaldeep

    2016-03-01

    A series of benzimidazole-based quinazoline derivatives with different substitutions of primary and secondary amines at the C2 position (1-12) were evaluated for their Aurora kinase inhibitory activities. All compounds except for 3 and 6 showed good activity against Aurora kinase inhibitors, with IC50 values in the range of 0.035-0.532 μM. The ligand efficiency (LE) of the compounds with Aurora A kinase was also determined. The structure-activity relationship and the quantitative structure-activity relationship revealed that the Aurora inhibitory activities of these derivatives primarily depend on the different substitutions of the amine present at the C2 position of the quinazoline core. Molecular docking studies in the active binding site also provided theoretical support for the experimental biological data acquired. The current study identifies a novel class of Aurora kinase inhibitors, which can further be used for the treatment of cancer.

  13. Estimating the Potential Toxicity of Chemicals Associated with Hydraulic Fracturing Operations Using Quantitative Structure-Activity Relationship Modeling.

    PubMed

    Yost, Erin E; Stanek, John; DeWoskin, Robert S; Burgoon, Lyle D

    2016-07-19

    The United States Environmental Protection Agency (EPA) identified 1173 chemicals associated with hydraulic fracturing fluids, flowback, or produced water, of which 1026 (87%) lack chronic oral toxicity values for human health assessments. To facilitate the ranking and prioritization of chemicals that lack toxicity values, it may be useful to employ toxicity estimates from quantitative structure-activity relationship (QSAR) models. Here we describe an approach for applying the results of a QSAR model from the TOPKAT program suite, which provides estimates of the rat chronic oral lowest-observed-adverse-effect level (LOAEL). Of the 1173 chemicals, TOPKAT was able to generate LOAEL estimates for 515 (44%). To address the uncertainty associated with these estimates, we assigned qualitative confidence scores (high, medium, or low) to each TOPKAT LOAEL estimate, and found 481 to be high-confidence. For 48 chemicals that had both a high-confidence TOPKAT LOAEL estimate and a chronic oral reference dose from EPA's Integrated Risk Information System (IRIS) database, Spearman rank correlation identified 68% agreement between the two values (permutation p-value =1 × 10(-11)). These results provide support for the use of TOPKAT LOAEL estimates in identifying and prioritizing potentially hazardous chemicals. High-confidence TOPKAT LOAEL estimates were available for 389 of 1026 hydraulic fracturing-related chemicals that lack chronic oral RfVs and OSFs from EPA-identified sources, including a subset of chemicals that are frequently used in hydraulic fracturing fluids. PMID:27172125

  14. Estimating the Potential Toxicity of Chemicals Associated with Hydraulic Fracturing Operations Using Quantitative Structure-Activity Relationship Modeling.

    PubMed

    Yost, Erin E; Stanek, John; DeWoskin, Robert S; Burgoon, Lyle D

    2016-07-19

    The United States Environmental Protection Agency (EPA) identified 1173 chemicals associated with hydraulic fracturing fluids, flowback, or produced water, of which 1026 (87%) lack chronic oral toxicity values for human health assessments. To facilitate the ranking and prioritization of chemicals that lack toxicity values, it may be useful to employ toxicity estimates from quantitative structure-activity relationship (QSAR) models. Here we describe an approach for applying the results of a QSAR model from the TOPKAT program suite, which provides estimates of the rat chronic oral lowest-observed-adverse-effect level (LOAEL). Of the 1173 chemicals, TOPKAT was able to generate LOAEL estimates for 515 (44%). To address the uncertainty associated with these estimates, we assigned qualitative confidence scores (high, medium, or low) to each TOPKAT LOAEL estimate, and found 481 to be high-confidence. For 48 chemicals that had both a high-confidence TOPKAT LOAEL estimate and a chronic oral reference dose from EPA's Integrated Risk Information System (IRIS) database, Spearman rank correlation identified 68% agreement between the two values (permutation p-value =1 × 10(-11)). These results provide support for the use of TOPKAT LOAEL estimates in identifying and prioritizing potentially hazardous chemicals. High-confidence TOPKAT LOAEL estimates were available for 389 of 1026 hydraulic fracturing-related chemicals that lack chronic oral RfVs and OSFs from EPA-identified sources, including a subset of chemicals that are frequently used in hydraulic fracturing fluids.

  15. Discovering Anti-platelet Drug Combinations with an Integrated Model of Activator-Inhibitor Relationships, Activator-Activator Synergies and Inhibitor-Inhibitor Synergies

    PubMed Central

    Lombardi, Federica; Golla, Kalyan; Fitzpatrick, Darren J.; Casey, Fergal P.; Moran, Niamh; Shields, Denis C.

    2015-01-01

    Identifying effective therapeutic drug combinations that modulate complex signaling pathways in platelets is central to the advancement of effective anti-thrombotic therapies. However, there is no systems model of the platelet that predicts responses to different inhibitor combinations. We developed an approach which goes beyond current inhibitor-inhibitor combination screening to efficiently consider other signaling aspects that may give insights into the behaviour of the platelet as a system. We investigated combinations of platelet inhibitors and activators. We evaluated three distinct strands of information, namely: activator-inhibitor combination screens (testing a panel of inhibitors against a panel of activators); inhibitor-inhibitor synergy screens; and activator-activator synergy screens. We demonstrated how these analyses may be efficiently performed, both experimentally and computationally, to identify particular combinations of most interest. Robust tests of activator-activator synergy and of inhibitor-inhibitor synergy required combinations to show significant excesses over the double doses of each component. Modeling identified multiple effects of an inhibitor of the P2Y12 ADP receptor, and complementarity between inhibitor-inhibitor synergy effects and activator-inhibitor combination effects. This approach accelerates the mapping of combination effects of compounds to develop combinations that may be therapeutically beneficial. We integrated the three information sources into a unified model that predicted the benefits of a triple drug combination targeting ADP, thromboxane and thrombin signaling. PMID:25875950

  16. Structure-activity relationships for biodistribution, pharmacokinetics, and excretion of atomically precise nanoclusters in a murine model

    NASA Astrophysics Data System (ADS)

    Wong, O. Andrea; Hansen, Ryan J.; Ni, Thomas W.; Heinecke, Christine L.; Compel, W. Scott; Gustafson, Daniel L.; Ackerson, Christopher J.

    2013-10-01

    The absorption, distribution, metabolism and excretion (ADME) and pharmacokinetic (PK) properties of inorganic nanoparticles with hydrodynamic diameters between 2 and 20 nm are presently unpredictable. It is unclear whether unpredictable in vivo properties and effects arise from a subset of molecules in a nanomaterials preparation, or if the ADME/PK properties are ensemble properties of an entire preparation. Here we characterize the ADME/PK properties of atomically precise preparations of ligand protected gold nanoclusters in a murine model system. We constructed atomistic models and tested in vivo properties for five well defined compounds, based on crystallographically resolved Au25(SR)18 and Au102(SR)44 nanoclusters with different (SR) ligand shells. To rationalize unexpected distribution and excretion properties observed for several clusters in this study and others, we defined a set of atomistic structure-activity relationships (SAR) for nanoparticles, which includes previously investigated parameters such as particle hydrodynamic diameter and net charge, and new parameters such as hydrophobic surface area and surface charge density. Overall we find that small changes in particle formulation can provoke dramatic yet potentially predictable changes in ADME/PK.The absorption, distribution, metabolism and excretion (ADME) and pharmacokinetic (PK) properties of inorganic nanoparticles with hydrodynamic diameters between 2 and 20 nm are presently unpredictable. It is unclear whether unpredictable in vivo properties and effects arise from a subset of molecules in a nanomaterials preparation, or if the ADME/PK properties are ensemble properties of an entire preparation. Here we characterize the ADME/PK properties of atomically precise preparations of ligand protected gold nanoclusters in a murine model system. We constructed atomistic models and tested in vivo properties for five well defined compounds, based on crystallographically resolved Au25(SR)18 and Au102(SR

  17. Structure-guided unravelling: Phenolic hydroxyls contribute to reduction of acrylamide using multiplex quantitative structure-activity relationship modelling.

    PubMed

    Zhang, Yu; Huang, Mengmeng; Wang, Qiao; Cheng, Jun

    2016-05-15

    We reported a structure-activity relationship study on unravelling phenolic hydroxyls instead of alcoholic hydroxyls contribute to the reduction of acrylamide formation by flavonoids. The dose-dependent study shows a close correlation between the number of phenolic hydroxyls of flavonoids and their reduction effects. In view of positions of hydroxyls, the 3',4'(ortho)-dihydroxyls in B cycle, 3-hydroxyl or hydroxyls of 3-gallate in C cycle, and 5,7(meta)-dihydroxyls in A cycle of flavonoid structures play an important role in the reduction of acrylamide. Flavone C-glycosides are more effective at reducing the formation of acrylamide than flavone O-glycosides when sharing the same aglycone. The current multiplex quantitative structure-activity relationship (QSAR) equations effectively predict the inhibitory rates of acrylamide using selected chemometric parameters (R(2): 0.835-0.938). This pioneer study opens a broad understanding on the chemoprevention of acrylamide contaminants on a structural basis.

  18. Pyrrolo[1,3]benzothiazepine-based atypical antipsychotic agents. Synthesis, structure-activity relationship, molecular modeling, and biological studies.

    PubMed

    Campiani, Giuseppe; Butini, Stefania; Gemma, Sandra; Nacci, Vito; Fattorusso, Caterina; Catalanotti, Bruno; Giorgi, Gianluca; Cagnotto, Alfredo; Goegan, Mara; Mennini, Tiziana; Minetti, Patrizia; Di Cesare, M Assunta; Mastroianni, Domenico; Scafetta, Nazzareno; Galletti, Bruno; Stasi, M Antonietta; Castorina, Massimo; Pacifici, Licia; Ghirardi, Orlando; Tinti, Ornella; Carminati, Paolo

    2002-01-17

    The prototypical dopamine and serotonin antagonist (+/-)-7-chloro-9-(4-methylpiperazin-1-yl)-9,10-dihydropyrrolo[2,1-b][1,3]benzothiazepine (5) was resolved into its R and S enantiomers via crystallization of the diastereomeric tartaric acid salts. Binding studies confirmed that the (R)-(-)-enantiomer is a more potent D(2) receptor antagonist than the (S)-(+)-enantiomer, with almost identical affinity at the 5-HT(2) receptor ((S)-(+)-5, log Y = 4.7; (R)-(-)-5, log Y = 7.4). These data demonstrated a significant stereoselective interaction of 5 at D(2) receptors. Furthermore, enantiomer (S)-(+)-5 (ST1460) was tested on a panel of receptors; this compound showed an intriguing binding profile characterized by high affinity for H(1) and the alpha(1) receptor, a moderate affinity for alpha(2) and D(3) receptors, and low affinity for muscarinic receptors. Pharmacological and biochemical investigation confirmed an atypical pharmacological profile for (S)-(+)-5. This atypical antipsychotic lead has low propensity to induce catalepsy in rat. It has minimal effect on serum prolactin levels, and it has been selected for further pharmacological studies. (S)-(+)-5 increases the extracellular levels of dopamine in the rat striatum after subcutaneous administration. By use of 5 as the lead compound, a novel series of potential atypical antipsychotics has been developed, some of them being characterized by a stereoselective interaction at D(2) receptors. A number of structure-activity relationships trends have been identified, and a possible explanation is advanced in order to account for the observed stereoselectivity of the enantiomer of (+/-)-5 for D(2) receptors. The molecular structure determination of the enantiomers of 5 by X-ray diffraction and molecular modeling is reported. PMID:11784139

  19. Orally Active Metabotropic Glutamate Subtype 2 Receptor Positive Allosteric Modulators: Structure-Activity Relationships and Assessment in a Rat Model of Nicotine Dependence

    PubMed Central

    Sidique, Shyama; Dhanya, Raveendra-Panickar; Sheffler, Douglas J.; Nickols, Hilary Highfield; Yang, Li; Dahl, Russell; Mangravita-Novo, Arianna; Smith, Layton H.; D’Souza, Manoranjan S.; Semenova, Svetlana; Conn, P. Jeffrey; Markou, Athina; Cosford, Nicholas D. P.

    2012-01-01

    Compounds that modulate metabotropic glutamate subtype 2 (mGlu2) receptors have the potential to treat several disorders of the central nervous system (CNS) including drug dependence. Herein we describe the synthesis and structure-activity relationship (SAR) studies around a series of mGlu2 receptor positive allosteric modulators (PAMs). The effects of N-substitution (R1) and substitutions on the aryl ring (R2) were identified as key areas for SAR exploration (Figure 3). Investigation of the effects of varying substituents in both the isoindolinone (2) and benzisothiazolone (3) series led to compounds with improved in vitro potency and/or efficacy. In addition, several analogues exhibited promising pharmacokinetic (PK) properties. Furthermore, compound 2 was shown to dose-dependently decrease nicotine self-administration in rats following oral administration. Our data, showing for the first time efficacy of an mGlu2 receptor PAM in this in vivo model, suggest potential utility for the treatment of nicotine dependence in humans. PMID:23009245

  20. Parabolic quantitative structure-activity relationships and photodynamic therapy: application of a three-compartment model with clearance to the in vivo quantitative structure-activity relationships of a congeneric series of pyropheophorbide derivatives used as photosensitizers for photodynamic therapy.

    PubMed

    Potter, W R; Henderson, B W; Bellnier, D A; Pandey, R K; Vaughan, L A; Weishaupt, K R; Dougherty, T J

    1999-11-01

    An open three-compartment pharmacokinetic model was applied to the in vivo quantitative structure-activity relationship (QSAR) data of a homologous series of pyropheophorbide photosensitizers for photodynamic therapy (PDT). The physical model was a lipid compartment sandwiched between two identical aqueous compartments. The first compartment was assumed to clear irreversibly at a rate K0. The measured octanol-water partition coefficients, P(i) (where i is the number of carbons in the alkyl chain) and the clearance rate K0 determined the clearance kinetics of the drugs. Solving the coupled differential equations of the three-compartment model produced clearance kinetics for each of the sensitizers in each of the compartments. The third compartment was found to contain the target of PDT. This series of compounds is quite lipophilic. Therefore these drugs are found mainly in the second compartment. The drug level in the third compartment represents a small fraction of the tissue level and is thus not accessible to direct measurement by extraction. The second compartment of the model accurately predicted the clearance from the serum of mice of the hexyl ether of pyropheophorbide a, one member of this series of compounds. The diffusion and clearance rate constants were those found by fitting the pharmacokinetics of the third compartment to the QSAR data. This result validated the magnitude and mechanistic significance of the rate constants used to model the QSAR data. The PDT response to dose theory was applied to the kinetic behavior of the target compartment drug concentration. This produced a pharmacokinetic-based function connecting PDT response to dose as a function of time postinjection. This mechanistic dose-response function was fitted to published, single time point QSAR data for the pheophorbides. As a result, the PDT target threshold dose together with the predicted QSAR as a function of time postinjection was found.

  1. THE PRACTICE OF STRUCTURE ACTIVITY RELATIONSHIPS (SAR) IN TOXICOLOGY

    EPA Science Inventory

    Both qualitative and quantitative modeling methods relating chemical structure to biological activity, called structure-activity relationship analyses or SAR, are applied to the prediction and characterization of chemical toxicity. This minireview will discuss some generic issue...

  2. Further evaluation of quantitative structure--activity relationship models for the prediction of the skin sensitization potency of selected fragrance allergens.

    PubMed

    Patlewicz, Grace Y; Basketter, David A; Pease, Camilla K Smith; Wilson, Karen; Wright, Zoe M; Roberts, David W; Bernard, Guillaume; Arnau, Elena Giménez; Lepoittevin, Jean-Pierre

    2004-02-01

    Fragrance substances represent a very diverse group of chemicals; a proportion of them are associated with the ability to cause allergic reactions in the skin. Efforts to find substitute materials are hindered by the need to undertake animal testing for determining both skin sensitization hazard and potency. One strategy to avoid such testing is through an understanding of the relationships between chemical structure and skin sensitization, so-called structure-activity relationships. In recent work, we evaluated 2 groups of fragrance chemicals -- saturated aldehydes and alpha,beta-unsaturated aldehydes. Simple quantitative structure-activity relationship (QSAR) models relating the EC3 values [derived from the local lymph node assay (LLNA)] to physicochemical properties were developed for both sets of aldehydes. In the current study, we evaluated an additional group of carbonyl-containing compounds to test the predictive power of the developed QSARs and to extend their scope. The QSAR models were used to predict EC3 values of 10 newly selected compounds. Local lymph node assay data generated for these compounds demonstrated that the original QSARs were fairly accurate, but still required improvement. Development of these QSAR models has provided us with a better understanding of the potential mechanisms of action for aldehydes, and hence how to avoid or limit allergy. Knowledge generated from this work is being incorporated into new/improved rules for sensitization in the expert toxicity prediction system, deductive estimation of risk from existing knowledge (DEREK).

  3. Augmented multivariate image analysis applied to quantitative structure-activity relationship modeling of the phytotoxicities of benzoxazinone herbicides and related compounds on problematic weeds.

    PubMed

    Freitas, Mirlaine R; Matias, Stella V B G; Macedo, Renato L G; Freitas, Matheus P; Venturin, Nelson

    2013-09-11

    Two of major weeds affecting cereal crops worldwide are Avena fatua L. (wild oat) and Lolium rigidum Gaud. (rigid ryegrass). Thus, development of new herbicides against these weeds is required; in line with this, benzoxazinones, their degradation products, and analogues have been shown to be important allelochemicals and natural herbicides. Despite earlier structure-activity studies demonstrating that hydrophobicity (log P) of aminophenoxazines correlates to phytotoxicity, our findings for a series of benzoxazinone derivatives do not show any relationship between phytotoxicity and log P nor with other two usual molecular descriptors. On the other hand, a quantitative structure-activity relationship (QSAR) analysis based on molecular graphs representing structural shape, atomic sizes, and colors to encode other atomic properties performed very accurately for the prediction of phytotoxicities of these compounds against wild oat and rigid ryegrass. Therefore, these QSAR models can be used to estimate the phytotoxicity of new congeners of benzoxazinone herbicides toward A. fatua L. and L. rigidum Gaud.

  4. Mechanistic quantitative structure-activity relationship model for the photoinduced toxicity of polycyclic aromatic hydrocarbons. 1: Physical model based on chemical kinetics in a two-compartment system

    SciTech Connect

    Krylov, S.N.; Huang, X.D.; Zeiler, L.F.; Dixon, D.G.; Greenberg, B.M.

    1997-11-01

    A quantitative structure-activity relationship model for the photoinduced toxicity of 16 polycyclic aromatic hydrocarbons (PAHs) to duckweed (Lemna gibba) in simulated solar radiation (SSR) was developed. Lemna gibba was chosen for this study because toxicity could be considered in two compartments: water column and leaf tissue. Modeling of photoinduced toxicity was described by photochemical reactions between PAHs and a hypothetical group of endogenous biomolecules (G) required for normal growth, with damage to G by PAHs and/or photomodified PAHs in SSR resulting in impaired growth. The reaction scheme includes photomodification of PAHs, uptake of PAHs into leaves, triplet-state formation of intact PAHs, photosensitization reactions that damage G, and reactions between photomodified PAHs and G. The assumptions used were: the PAH photomodification rate is slower than uptake of chemicals into leaves, the PAH concentration in aqueous solution is nearly constant during a toxicity test, the fluence rate of actinic radiation is lower within leaves than in the aqueous phase, and the toxicity of intact PAHs in the dark is negligible. A series of differential equations describing the reaction kinetics of intact and photomodifed PAHs with G was derived. The resulting equation for PAH toxicity was a function of treatment period, initial PAH concentration, relative absorbance of SSR by each PAH, quantum yield for formation of triplet-state PAH, and rate of PAH photomodification. Data for growth in the presence of intact and photomodified PAHs were used to empirically solve for a photosensitization constant (PSC) and a photomodification constant (PMC) for each of the 16 PAHs tested. For 9 PAHs the PMC dominates and for 7 PAHs the PSC dominates.

  5. Novel phenolic inhibitors of the sarco/endoplasmic reticulum calcium ATPase: identification and characterization by quantitative structure-activity relationship modeling and virtual screening.

    PubMed

    Paula, Stefan; Hofmann, Emily; Burden, John; Stanton, David T

    2015-02-01

    Inhibitors of the sarco/endoplasmic reticulum calcium ATPase (SERCA) are valuable research tools and hold promise as a new generation of anti-prostate cancer agents. Based on previously determined potencies of phenolic SERCA inhibitors, we created quantitative structure-activity relationship (QSAR) models using three independent development strategies. The obtained QSAR models facilitated virtual screens of several commercial compound collections for novel inhibitors. Sixteen compounds were subsequently evaluated in SERCA activity inhibition assays and 11 showed detectable potencies in the micro- to millimolar range. The experimental results were then incorporated into a comprehensive master QSAR model, whose physical interpretation by partial least squares analysis revealed that properly positioned substituents at the central phenyl ring capable of forming hydrogen bonds and of undergoing hydrophobic interactions were prerequisites for effective SERCA inhibition. The established SAR was in good agreement with findings from previous structural studies, even though it was obtained independently using standard QSAR methodologies.

  6. A predictive quantitative structure-activity relationship model for the photoinduced toxicity of polycyclic aromatic hydrocarbons to Daphnia magna with the use of factors for photosensitization and photomodification.

    PubMed

    Lampi, Mark A; Gurska, Jolanta; Huang, Xiao-Dong; Dixon, D George; Greenberg, Bruce M

    2007-03-01

    Polycyclic aromatic hydrocarbons (PAHs) are ubiquitous environmental contaminants that readily absorb environmentally relevant solar ultraviolet radiation. On absorption of a photon, photoinduced toxicity of PAHs is manifested through photosensitization and photomodification. Both of these processes occur under environmentally relevant levels of actinic radiation. An empirical quantitative structure-activity relationship model previously developed was explanatory of photoinduced toxicity of 16 PAHs in Lemna gibba (duckweed). This model was found to be predictive of toxicity to Vibrio fischeri. The L. gibba quantitative structure-activity relationship showed that a photosensitization factor and a photomodification factor could be combined to describe photoinduced toxicity. To further examine this model, we assessed whether it could be applied to Daphnia magna (water flea), a key bioindicator species in aquatic ecosystems. Toxicity was assessed as median effective concentration and median effective time for immobility. As with L. gibba and V. fischeri, neither the photosensitization factor nor the photomodification factor alone correlated to toxicity in D. magna. However, a photosensitization factor modified for D. magna exhibited a correlation to toxicity (r2 = 0.86), which was modestly improved when summed with a modified photomodification factor (r2 = 0.92). The greatest correlation was observed with median effective concentration data. This research provides evidence that models incorporating factors for photosensitization and photomodification have interspecies applicability. PMID:17373503

  7. A predictive quantitative structure-activity relationship model for the photoinduced toxicity of polycyclic aromatic hydrocarbons to Daphnia magna with the use of factors for photosensitization and photomodification.

    PubMed

    Lampi, Mark A; Gurska, Jolanta; Huang, Xiao-Dong; Dixon, D George; Greenberg, Bruce M

    2007-03-01

    Polycyclic aromatic hydrocarbons (PAHs) are ubiquitous environmental contaminants that readily absorb environmentally relevant solar ultraviolet radiation. On absorption of a photon, photoinduced toxicity of PAHs is manifested through photosensitization and photomodification. Both of these processes occur under environmentally relevant levels of actinic radiation. An empirical quantitative structure-activity relationship model previously developed was explanatory of photoinduced toxicity of 16 PAHs in Lemna gibba (duckweed). This model was found to be predictive of toxicity to Vibrio fischeri. The L. gibba quantitative structure-activity relationship showed that a photosensitization factor and a photomodification factor could be combined to describe photoinduced toxicity. To further examine this model, we assessed whether it could be applied to Daphnia magna (water flea), a key bioindicator species in aquatic ecosystems. Toxicity was assessed as median effective concentration and median effective time for immobility. As with L. gibba and V. fischeri, neither the photosensitization factor nor the photomodification factor alone correlated to toxicity in D. magna. However, a photosensitization factor modified for D. magna exhibited a correlation to toxicity (r2 = 0.86), which was modestly improved when summed with a modified photomodification factor (r2 = 0.92). The greatest correlation was observed with median effective concentration data. This research provides evidence that models incorporating factors for photosensitization and photomodification have interspecies applicability.

  8. Virulence Factor-activity Relationships: Workshop Summary

    EPA Science Inventory

    The concept or notion of virulence factor–activity relationships (VFAR) is an approach for identifying an analogous process to the use of qualitative structure–activity relationships (QSAR) for identifying new microbial contaminants. In QSAR, it is hypothesized that, for new chem...

  9. Application of Quantitative Structure–Activity Relationship Models of 5-HT1A Receptor Binding to Virtual Screening Identifies Novel and Potent 5-HT1A Ligands

    PubMed Central

    2015-01-01

    The 5-hydroxytryptamine 1A (5-HT1A) serotonin receptor has been an attractive target for treating mood and anxiety disorders such as schizophrenia. We have developed binary classification quantitative structure–activity relationship (QSAR) models of 5-HT1A receptor binding activity using data retrieved from the PDSP Ki database. The prediction accuracy of these models was estimated by external 5-fold cross-validation as well as using an additional validation set comprising 66 structurally distinct compounds from the World of Molecular Bioactivity database. These validated models were then used to mine three major types of chemical screening libraries, i.e., drug-like libraries, GPCR targeted libraries, and diversity libraries, to identify novel computational hits. The five best hits from each class of libraries were chosen for further experimental testing in radioligand binding assays, and nine of the 15 hits were confirmed to be active experimentally with binding affinity better than 10 μM. The most active compound, Lysergol, from the diversity library showed very high binding affinity (Ki) of 2.3 nM against 5-HT1A receptor. The novel 5-HT1A actives identified with the QSAR-based virtual screening approach could be potentially developed as novel anxiolytics or potential antischizophrenic drugs. PMID:24410373

  10. Application of quantitative structure-activity relationship models of 5-HT1A receptor binding to virtual screening identifies novel and potent 5-HT1A ligands.

    PubMed

    Luo, Man; Wang, Xiang Simon; Roth, Bryan L; Golbraikh, Alexander; Tropsha, Alexander

    2014-02-24

    The 5-hydroxytryptamine 1A (5-HT1A) serotonin receptor has been an attractive target for treating mood and anxiety disorders such as schizophrenia. We have developed binary classification quantitative structure-activity relationship (QSAR) models of 5-HT1A receptor binding activity using data retrieved from the PDSP Ki database. The prediction accuracy of these models was estimated by external 5-fold cross-validation as well as using an additional validation set comprising 66 structurally distinct compounds from the World of Molecular Bioactivity database. These validated models were then used to mine three major types of chemical screening libraries, i.e., drug-like libraries, GPCR targeted libraries, and diversity libraries, to identify novel computational hits. The five best hits from each class of libraries were chosen for further experimental testing in radioligand binding assays, and nine of the 15 hits were confirmed to be active experimentally with binding affinity better than 10 μM. The most active compound, Lysergol, from the diversity library showed very high binding affinity (Ki) of 2.3 nM against 5-HT1A receptor. The novel 5-HT1A actives identified with the QSAR-based virtual screening approach could be potentially developed as novel anxiolytics or potential antischizophrenic drugs.

  11. Nano-quantitative structure-activity relationship modeling using easily computable and interpretable descriptors for uptake of magnetofluorescent engineered nanoparticles in pancreatic cancer cells.

    PubMed

    Kar, Supratik; Gajewicz, Agnieszka; Puzyn, Tomasz; Roy, Kunal

    2014-06-01

    As experimental evaluation of the safety of nanoparticles (NPs) is expensive and time-consuming, computational approaches have been found to be an efficient alternative for predicting the potential toxicity of new NPs before mass production. In this background, we have developed here a regression-based nano quantitative structure-activity relationship (nano-QSAR) model to establish statistically significant relationships between the measured cellular uptakes of 109 magnetofluorescent NPs in pancreatic cancer cells with their physical, chemical, and structural properties encoded within easily computable, interpretable and reproducible descriptors. The developed model was rigorously validated internally as well as externally with the application of the principles of Organization for Economic Cooperation and Development (OECD). The test for domain of applicability was also carried out for checking reliability of the predictions. Important fragments contributing to higher/lower cellular uptake of NPs were identified through critical analysis and interpretation of the developed model. Considering all these identified structural attributes, one can choose or design safe, economical and suitable surface modifiers for NPs. The presented approach provides rich information in the context of virtual screening of relevant NP libraries.

  12. Nano-quantitative structure-activity relationship modeling using easily computable and interpretable descriptors for uptake of magnetofluorescent engineered nanoparticles in pancreatic cancer cells.

    PubMed

    Kar, Supratik; Gajewicz, Agnieszka; Puzyn, Tomasz; Roy, Kunal

    2014-06-01

    As experimental evaluation of the safety of nanoparticles (NPs) is expensive and time-consuming, computational approaches have been found to be an efficient alternative for predicting the potential toxicity of new NPs before mass production. In this background, we have developed here a regression-based nano quantitative structure-activity relationship (nano-QSAR) model to establish statistically significant relationships between the measured cellular uptakes of 109 magnetofluorescent NPs in pancreatic cancer cells with their physical, chemical, and structural properties encoded within easily computable, interpretable and reproducible descriptors. The developed model was rigorously validated internally as well as externally with the application of the principles of Organization for Economic Cooperation and Development (OECD). The test for domain of applicability was also carried out for checking reliability of the predictions. Important fragments contributing to higher/lower cellular uptake of NPs were identified through critical analysis and interpretation of the developed model. Considering all these identified structural attributes, one can choose or design safe, economical and suitable surface modifiers for NPs. The presented approach provides rich information in the context of virtual screening of relevant NP libraries. PMID:24412539

  13. Using quantitative structure activity relationship models to predict an appropriate solvent system from a common solvent system family for countercurrent chromatography separation.

    PubMed

    Marsden-Jones, Siân; Colclough, Nicola; Garrard, Ian; Sumner, Neil; Ignatova, Svetlana

    2015-06-12

    Countercurrent chromatography (CCC) is a form of liquid-liquid chromatography. It works by running one immiscible solvent (mobile phase) over another solvent (stationary phase) being held in a CCC column using centrifugal force. The concentration of compound in each phase is characterised by the partition coefficient (Kd), which is the concentration in the stationary phase divided by the concentration in the mobile phase. When Kd is between approximately 0.2 and 2, it is most likely that optimal separation will be achieved. Having the Kd in this range allows the compound enough time in the column to be separated without resulting in a broad peak and long run time. In this paper we report the development of quantitative structure activity relationship (QSAR) models to predict logKd. The QSAR models use only the molecule's 2D structure to predict the molecular property logKd.

  14. Novel potent and selective bile acid derivatives as TGR5 agonists: biological screening, structure-activity relationships, and molecular modeling studies.

    PubMed

    Sato, Hiroyuki; Macchiarulo, Antonio; Thomas, Charles; Gioiello, Antimo; Une, Mizuho; Hofmann, Alan F; Saladin, Régis; Schoonjans, Kristina; Pellicciari, Roberto; Auwerx, Johan

    2008-03-27

    TGR5, a metabotropic receptor that is G-protein-coupled to the induction of adenylate cyclase, has been recognized as the molecular link connecting bile acids to the control of energy and glucose homeostasis. With the aim of disclosing novel selective modulators of this receptor and at the same time clarifying the molecular basis of TGR5 activation, we report herein the biological screening of a collection of natural occurring bile acids, bile acid derivatives, and some steroid hormones, which has resulted in the discovery of new potent and selective TGR5 ligands. Biological results of the tested collection of compounds were used to extend the structure-activity relationships of TGR5 agonists and to develop a binary classification model of TGR5 activity. This model in particular could unveil some hidden properties shared by the molecular shape of bile acids and steroid hormones that are relevant to TGR5 activation and may hence be used to address the design of novel selective and potent TGR5 agonists.

  15. The use of quantitative structure-activity relationship models to develop optimized processes for the removal of tobacco host cell proteins during biopharmaceutical production.

    PubMed

    Buyel, J F; Woo, J A; Cramer, S M; Fischer, R

    2013-12-27

    The production of recombinant pharmaceutical proteins in plants benefits from the low cost of upstream production and the greater scalability of plants compared to fermenter-based systems. Now that manufacturing processes that comply with current good manufacturing practices have been developed, plants can compete with established platforms on equal terms. However, the costs of downstream processing remain high, in part because of the dedicated process steps required to remove plant-specific process-related impurities. We therefore investigated whether the ideal strategy for the chromatographic removal of tobacco host cell proteins can be predicted by quantitative structure-activity relationship (QSAR) modeling to reduce the process development time and overall costs. We identified more than 100 tobacco proteins by mass spectrometry and their structures were reconstructed from X-ray crystallography, nuclear magnetic resonance spectroscopy and/or homology modeling data. The resulting three-dimensional models were used to calculate protein descriptors, and significant descriptors were selected based on recently-published retention data for model proteins to develop QSAR models for protein retention on anion, cation and mixed-mode resins. The predicted protein retention profiles were compared with experimental results using crude tobacco protein extracts. Because of the generic nature of the method, it can easily be transferred to other expression systems such as mammalian cells. The quality of the models and potential improvements are discussed.

  16. The use of quantitative structure-activity relationship models to develop optimized processes for the removal of tobacco host cell proteins during biopharmaceutical production.

    PubMed

    Buyel, J F; Woo, J A; Cramer, S M; Fischer, R

    2013-12-27

    The production of recombinant pharmaceutical proteins in plants benefits from the low cost of upstream production and the greater scalability of plants compared to fermenter-based systems. Now that manufacturing processes that comply with current good manufacturing practices have been developed, plants can compete with established platforms on equal terms. However, the costs of downstream processing remain high, in part because of the dedicated process steps required to remove plant-specific process-related impurities. We therefore investigated whether the ideal strategy for the chromatographic removal of tobacco host cell proteins can be predicted by quantitative structure-activity relationship (QSAR) modeling to reduce the process development time and overall costs. We identified more than 100 tobacco proteins by mass spectrometry and their structures were reconstructed from X-ray crystallography, nuclear magnetic resonance spectroscopy and/or homology modeling data. The resulting three-dimensional models were used to calculate protein descriptors, and significant descriptors were selected based on recently-published retention data for model proteins to develop QSAR models for protein retention on anion, cation and mixed-mode resins. The predicted protein retention profiles were compared with experimental results using crude tobacco protein extracts. Because of the generic nature of the method, it can easily be transferred to other expression systems such as mammalian cells. The quality of the models and potential improvements are discussed. PMID:24268820

  17. Diarylsulfonamides and their bioisosteres as dual inhibitors of alkaline phosphatase and carbonic anhydrase: Structure activity relationship and molecular modelling studies.

    PubMed

    Al-Rashida, Mariya; Ejaz, Syeda Abida; Ali, Sharafat; Shaukat, Aisha; Hamayoun, Mehwish; Ahmed, Maqsood; Iqbal, Jamshed

    2015-05-15

    The effect of bioisosteric replacement of carboxamide linking group with sulfonamide linking group, on alkaline phosphatase (AP) and carbonic anhydrase (CA) inhibition activity of aromatic benzenesulfonamides was investigated. A series of carboxamide linked aromatic benzenesulfonamides 1a-1c, 2a-2d and their sulfonamide linked bioisosteres 3a-3d, 4a-4d was synthesized and evaluated for inhibitory activity against bovine tissue non-specific alkaline phosphatase (TNAP), intestinal alkaline phosphatase (IAP) and bCA II. A significant increase in CA inhibition activity was observed upon bioisosteric replacement of carboxamide linking group with a sulfonamide group. Some of these compounds were identified as highly potent and selective AP inhibitors. Compounds 1b, 2b, 3d, 4d 5b and 5c were found to be selective bTNAP inhibitors, whereas compounds 1a, 1c, 2a, 2c, 2d, 3a, 3c, 4a, 4b, 4c, 5a were found to be selective bIAP inhibitors. For most active AP inhibitor 3b, detailed kinetic studies indicated a competitive mode of inhibition against tissue non-specific alkaline phosphatase (TNAP) and non-competitive mode of inhibition against intestinal alkaline phosphatase (IAP). Molecular docking studies were carried out to rationalize important binding site interactions. PMID:25865133

  18. Diarylsulfonamides and their bioisosteres as dual inhibitors of alkaline phosphatase and carbonic anhydrase: Structure activity relationship and molecular modelling studies.

    PubMed

    Al-Rashida, Mariya; Ejaz, Syeda Abida; Ali, Sharafat; Shaukat, Aisha; Hamayoun, Mehwish; Ahmed, Maqsood; Iqbal, Jamshed

    2015-05-15

    The effect of bioisosteric replacement of carboxamide linking group with sulfonamide linking group, on alkaline phosphatase (AP) and carbonic anhydrase (CA) inhibition activity of aromatic benzenesulfonamides was investigated. A series of carboxamide linked aromatic benzenesulfonamides 1a-1c, 2a-2d and their sulfonamide linked bioisosteres 3a-3d, 4a-4d was synthesized and evaluated for inhibitory activity against bovine tissue non-specific alkaline phosphatase (TNAP), intestinal alkaline phosphatase (IAP) and bCA II. A significant increase in CA inhibition activity was observed upon bioisosteric replacement of carboxamide linking group with a sulfonamide group. Some of these compounds were identified as highly potent and selective AP inhibitors. Compounds 1b, 2b, 3d, 4d 5b and 5c were found to be selective bTNAP inhibitors, whereas compounds 1a, 1c, 2a, 2c, 2d, 3a, 3c, 4a, 4b, 4c, 5a were found to be selective bIAP inhibitors. For most active AP inhibitor 3b, detailed kinetic studies indicated a competitive mode of inhibition against tissue non-specific alkaline phosphatase (TNAP) and non-competitive mode of inhibition against intestinal alkaline phosphatase (IAP). Molecular docking studies were carried out to rationalize important binding site interactions.

  19. QUANTITATIVE STRUCTURE-ACTIVITY RELATIONSHIP MODELS FOR PREDICTION OF ESTROGEN RECEPTOR BINDING AFFINITY OF STRUCTURALLY DIVERSE CHEMICALS

    EPA Science Inventory

    The demonstrated ability of a variety of structurally diverse chemicals to bind to the estrogen receptor has raised the concern that chemicals in the environment may be causing adverse effects through interference with nuclear receptor pathways. Many structure-activity relationsh...

  20. Quantitative structure-activity relationship modeling of juvenile hormone mimetic compounds for Culex pipiens larvae, with a discussion of descriptor-thinning methods.

    PubMed

    Basak, Subhash C; Natarajan, Ramanathan; Mills, Denise; Hawkins, Douglas M; Kraker, Jessica J

    2006-01-01

    Quantitative structure-activity relationship (QSAR) modelers often encounter the problem of multicollinearity owing to the availability of large numbers of computable molecular descriptors. Sparsity of the variables while using descriptors such as atom pairs increases the complexity. Three different predictor-thinning methods, namely, a modified Gram-Schmidt algorithm, a marginal soft thresholding algorithm, and LASSO (least absolute shrinkage and selection operator), were utilized to reduce the number of descriptors prior to developing linear models. Juvenile hormone (JH) activity of 304 compounds on Culex pipiens larvae was taken as the model data set, and predictor trimming of a large number of diverse descriptors comprising 268 global molecular descriptors (topostructural, topochemical, and geometrical), 13 quantum chemical descriptors, and 915 atom pairs (substructural counts) was applied prior to linear regression by the ridge regression method. The data set (N = 304) was split into five calibration data sets of random samples of sizes 60/110/160/210/260, and the remaining 244/194/144/94/44 compounds were used for validations. LASSO was not found to be a very effective method in handling a large set of descriptors because the number of predictors retained could not exceed the number of observations. The results indicated that the modified Gram-Schmidt algorithm could be used to trim the number of predictors in the global molecular descriptor set where collinearity of the descriptors was the major concern. On the contrary, the soft thresholding approach was found to be an effective tool in subset selection from a diverse set of descriptors having both sparsity and multicollinearity, as in the case of the combined set of atom pairs and global molecular descriptors. The final model developed after variable selection was dominated more by atom pairs, which indicated the important structural moieties that affect JH activity of the compounds. The success of the

  1. Structure-activity relationships of seco-prezizaane and picrotoxane/picrodendrane terpenoids by Quasar receptor-surface modeling.

    PubMed

    Schmidt, Thomas J; Gurrath, Marion; Ozoe, Yoshihisa

    2004-08-01

    The seco-prezizaane-type sesquiterpenes pseudoanisatin and parviflorolide from Illicium are noncompetitive antagonists at housefly (Musca domestica) gamma-aminobutyric acid (GABA) receptors. They show selectivity toward the insect receptor and thus represent new leads toward selective insecticides. Based on the binding data for 13 seco-prezizaane terpenoids and 17 picrotoxane and picrodendrane-type terpenoids to housefly and rat GABA receptors, a QSAR study was conducted by quasi-atomistic receptor-surface modeling (Quasar). The resulting models provide insight into the structural basis of selectivity and properties of the binding sites at GABA receptor-coupled chloride channels of insects and mammals.

  2. Quantitative structure activity relationship model for predicting the depletion percentage of skin allergic chemical substances of glutathione.

    PubMed

    Si, Hongzong; Wang, Tao; Zhang, Kejun; Duan, Yun-Bo; Yuan, Shuping; Fu, Aiping; Hu, Zhide

    2007-05-22

    A quantitative model was developed to predict the depletion percentage of glutathione (DPG) compounds by gene expression programming (GEP). Each kind of compound was represented by several calculated structural descriptors involving constitutional, topological, geometrical, electrostatic and quantum-chemical features of compounds. The GEP method produced a nonlinear and five-descriptor quantitative model with a mean error and a correlation coefficient of 10.52 and 0.94 for the training set, 22.80 and 0.85 for the test set, respectively. It is shown that the GEP predicted results are in good agreement with experimental ones, better than those of the heuristic method.

  3. Quantitative structure-activity relationship models for predicting drug-induced liver injury based on FDA-approved drug labeling annotation and using a large collection of drugs.

    PubMed

    Chen, Minjun; Hong, Huixiao; Fang, Hong; Kelly, Reagan; Zhou, Guangxu; Borlak, Jürgen; Tong, Weida

    2013-11-01

    Drug-induced liver injury (DILI) is one of the leading causes of the termination of drug development programs. Consequently, identifying the risk of DILI in humans for drug candidates during the early stages of the development process would greatly reduce the drug attrition rate in the pharmaceutical industry but would require the implementation of new research and development strategies. In this regard, several in silico models have been proposed as alternative means in prioritizing drug candidates. Because the accuracy and utility of a predictive model rests largely on how to annotate the potential of a drug to cause DILI in a reliable and consistent way, the Food and Drug Administration-approved drug labeling was given prominence. Out of 387 drugs annotated, 197 drugs were used to develop a quantitative structure-activity relationship (QSAR) model and the model was subsequently challenged by the left of drugs serving as an external validation set with an overall prediction accuracy of 68.9%. The performance of the model was further assessed by the use of 2 additional independent validation sets, and the 3 validation data sets have a total of 483 unique drugs. We observed that the QSAR model's performance varied for drugs with different therapeutic uses; however, it achieved a better estimated accuracy (73.6%) as well as negative predictive value (77.0%) when focusing only on these therapeutic categories with high prediction confidence. Thus, the model's applicability domain was defined. Taken collectively, the developed QSAR model has the potential utility to prioritize compound's risk for DILI in humans, particularly for the high-confidence therapeutic subgroups like analgesics, antibacterial agents, and antihistamines.

  4. Relationship between subthalamic nucleus neuronal activity and electrocorticogram is altered in the R6/2 mouse model of Huntington's disease

    PubMed Central

    Callahan, Joshua W; Abercrombie, Elizabeth D

    2015-01-01

    Huntington's disease (HD) is an autosomal dominant neurodegenerative disorder in which impairments in the processing of information between the cortex and basal ganglia are fundamental to the onset and progression of the HD phenotype. The corticosubthalamic hyperdirect pathway plays a pivotal role in motor selection and blockade of neuronal activity in the subthalamic nucleus (STN) results in a hyperkinetic movement syndrome, similar to the HD phenotype. The aim of the present study was to examine the relationship between neuronal activity in the STN and cortex in an animal model of HD. We performed in vivo extracellular recordings in the STN to measure single-unit activity and local field potentials in the R6/2 transgenic mouse model of HD. These recordings were obtained during epochs of simultaneously acquired electrocorticogram (ECoG) in discrete brain states representative of global cortical network synchronization or desynchronization. Cortically patterned STN neuronal activity was less phase-locked in R6/2 mice, which is likely to result in less efficient coding of cortical inputs by the basal ganglia. In R6/2 mice, the power of the ECoG in lower frequencies (0.5–4 Hz) was diminished while the power expressed in higher frequencies (13–100 Hz) was increased. In addition, the spontaneous activity of STN neurons in R6/2 mice was reduced and neurons exhibited a more irregular firing pattern. Glutamatergic STN neurons provide the major excitatory drive to the output nuclei of the basal ganglia and altered discharge patterns could lead to aberrant basal ganglia output and disordered motor control in HD. PMID:25952461

  5. Molecular analysis and structure-activity relationship modeling of the substrate/inhibitor interaction site of plasma membrane monoamine transporter.

    PubMed

    Ho, Horace T B; Pan, Yongmei; Cui, Zhiyi; Duan, Haichuan; Swaan, Peter W; Wang, Joanne

    2011-11-01

    Plasma membrane monoamine transporter (PMAT) is a new polyspecific transporter that interacts with a wide range of structurally diverse organic cations. To map the physicochemical descriptors of cationic compounds that allow interaction with PMAT, we systematically analyzed the interactions between PMAT and three series of structural analogs of known organic cation substrates including phenylalkylamines, n-tetraalkylammonium (n-TAA) compounds, and β-carbolines. Our results showed that phenylalkylamines with a distance between the aromatic ring and the positively charged amine nitrogen atom of ∼6.4 Å confer optimal interactions with PMAT, whereas studies with n-TAA compounds revealed an excellent correlation between IC(50) values and hydrophobicity. The five β-carbolines that we tested, which possess a pyridinium-like structure and are structurally related to the neurotoxin 1-methyl-4-phenylpyridinium, inhibited PMAT with high affinity (IC(50) values of 39.1-65.5 μM). Cytotoxicity analysis further showed that cells expressing PMAT are 14- to 15-fold more sensitive to harmalan and norharmanium, suggesting that these two β-carbolines are also transportable substrates of PMAT. We then used computer-aided modeling to generate qualitative and quantitative three-dimensional pharmacophore models on the basis of 23 previously reported and currently identified PMAT inhibitors and noninhibitors. These models are characterized by a hydrogen bond donor and two to three hydrophobic features with distances between the hydrogen bond donor and hydrophobic features ranging between 5.20 and 7.02 Å. The consistency between the mapping results and observed PMAT affinity of a set of test compounds indicates that the models performed well in inhibitor prediction and could be useful for future virtual screening of new PMAT inhibitors. PMID:21816955

  6. Stereospecific recognition and quantitative structure-activity relationship between antibodies and enantiomers: ofloxacin as a model hapten.

    PubMed

    Mu, Hongtao; Wang, Baoling; Xu, Zhenlin; Sun, Yuanming; Huang, Xinan; Shen, Yudong; Eremin, Sergei A; Zherdev, Anatoly V; Dzantiev, Boris B; Lei, Hongtao

    2015-02-21

    In this study, ofloxacin stereoisomers were chosen as a simple model to investigate the stereospecific recognition of chiral haptens and antibodies. Three polyclonal antibodies were studied and showed a relatively high enantioselectivity and an excellent sensitivity. Comparative molecular field analysis and comparative molecular similarity indices analysis were employed to investigate the chiral recognition between the antibody and the ofloxacin enantiomer, and all the models yielded high correlation and predictive ability. It was found that the chiral discrimination was probably caused by steric hindrance; the antibody stereospecificity could be ascribed to the variation of the R1 and R3 groups of quinolones; the common structure of the quinolones is also essential in the hapten-antibody recognition. The recognition between the chiral haptens and the antibodies was co-affected by multiple interaction forces, and those forces were defined explicitly at the sub-structural level. An illustrative enhanced model with good simplicity and universality was also developed for a better understanding of the stereospecific recognition of ofloxacin enantiomers and antibodies for the first time. This work provides insights into the stereospecific recognition of chiral haptens and antibodies.

  7. Structure-activity relationships of the antimicrobial peptide gramicidin S and its analogs: aqueous solubility, self-association, conformation, antimicrobial activity and interaction with model lipid membranes.

    PubMed

    Abraham, Thomas; Prenner, Elmar J; Lewis, Ruthven N A H; Mant, Colin T; Keller, Sandro; Hodges, Robert S; McElhaney, Ronald N

    2014-05-01

    GS10 [cyclo-(VKLdYPVKLdYP)] is a synthetic analog of the naturally occurring antimicrobial peptide gramicidin (GS) in which the two positively charged ornithine (Orn) residues are replaced by two positively charged lysine (Lys) residues and the two less polar aromatic phenylalanine (Phe) residues are replaced by the more polar tyrosine (Tyr) residues. In this study, we examine the effects of these seemingly conservative modifications to the parent GS molecule on the physical properties of the peptide, and on its interactions with lipid bilayer model and biological membranes, by a variety of biophysical techniques. We show that although GS10 retains the largely β-sheet conformation characteristic of GS, it is less structured in both water and membrane-mimetic solvents. GS10 is also more water soluble and less hydrophobic than GS, as predicted, and also exhibits a reduced tendency for self-association in aqueous solution. Surprisingly, GS10 associates more strongly with zwitterionic and anionic phospholipid bilayer model membranes than does GS, despite its greater water solubility, and the presence of anionic phospholipids and cholesterol (Chol) modestly reduces the association of both GS10 and GS to these model membranes. The strong partitioning of both peptides into lipid bilayers is driven by a large favorable entropy change opposed by a much smaller unfavorable enthalpy change. However, GS10 is also less potent than GS at inducing inverted cubic phases in phospholipid bilayer model membranes and at inhibiting the growth of the cell wall-less bacterium Acholeplasma laidlawii B. These results are discussed in terms of the comparative antibiotic and hemolytic activities of these peptides.

  8. Social Relationships, Leisure Activity, and Health in Older Adults

    PubMed Central

    Chang, Po-Ju; Wray, Linda; Lin, Yeqiang

    2015-01-01

    Objective Although the link between enhanced social relationships and better health has generally been well established, few studies have examined the role of leisure activity in this link. This study examined how leisure influences the link between social relationships and health in older age. Methods Using data from the 2006 and 2010 waves of the nationally representative U.S. Health and Retirement Study and structural equation modelling analyses, we examined data on 2,965 older participants to determine if leisure activities mediated the link between social relationships and health in 2010, controlling for race, education level, and health in 2006. Results The results demonstrated that leisure activities mediate the link between social relationships and health in these age groups. Perceptions of positive social relationships were associated with greater involvement in leisure activities, and greater involvement in leisure activities was associated with better health in older age. Discussion & Conclusions The contribution of leisure to health in these age groups is receiving increasing attention, and the results of this study add to the literature on this topic, by identifying the mediating effect of leisure activity on the link between social relationships and health. Future studies aimed at increasing leisure activity may contribute to improved health outcomes in older adults. PMID:24884905

  9. Combined Toxic Effects of Polar and Nonpolar Chemicals on Human Hepatocytes (HepG2) Cells by Quantitative Property-Activity Relationship Modeling

    PubMed Central

    Kim, Ki-Woong; Won, Yong Lim; Park, Dong Jin; Kim, Young Sun; Jin, Eun Sil; Lee, Sung Kwang

    2016-01-01

    We determined the toxicity of mixtures of ethyl acetate (EA), isopropyl alcohol (IPA), methyl ethyl ketone (MEK), toluene (TOL) and xylene (XYL) with half-maximal effective concentration (EC50) values obtained using human hepatocytes cells. According to these data, quantitative property-activity relationships (QPAR) models were successfully proposed to predict the toxicity of mixtures by multiple linear regressions (MLR). The leave-one-out cross validation method was used to find the best subsets of descriptors in the learning methods. Significant differences in physico-chemical properties such as boiling point (BP), specific gravity (SG), Reid vapor pressure (rVP) and flash point (FP) were observed between the single substances and the mixtures. The EC50 of the mixture of EA and IPA was significantly lower than that of contained TOL and XYL. The mixture toxicity was related to the mixing ratio of MEK, TOL and XYL (MLR equation EC50 = 3.3081 − 2.5018 × TOL − 3.2595 × XYL − 12.6596 × MEK × XYL), as well as to BP, SG, VP and FP (MLR equation EC50 = 1.3424 + 6.2250 × FP − 7.1198 × SG × FP − 0.03013 × rVP × FP). These results suggest that QPAR-based models could accurately predict the toxicity of polar and nonpolar mixtures used in rotogravure printing industries.

  10. Relationships between solar activity and climate change

    NASA Technical Reports Server (NTRS)

    Roberts, W. O.

    1975-01-01

    The relationship between recurrent droughts in the High Plains of the United States and the double sunspot cycle is discussed in detail. It is suggested that high solar activity is generally related to an increase in meridional circulation and blocking patterns at high and intermediate latitudes, especially in winter, and the effect is related to the sudden formation of cirrus clouds during strong geomagnetic activity that originates in the solar corpuscular emission.

  11. Quantitative genetic analysis of causal relationships among feather pecking, feather eating, and general locomotor activity in laying hens using structural equation models.

    PubMed

    Lutz, V; Kjaer, J B; Iffland, H; Rodehutscord, M; Bessei, W; Bennewitz, J

    2016-08-01

    The objective of this research was to analyze the relationship between feather pecking (FP) and feather eating (FE) as well as general locomotor activity (GLA) using structural equation models, which allow that one trait can be treated as an explanatory variable of another trait. This provides an opportunity to infer putative causal links among the traits. For the analysis, 897 F2-hens set up from 2 lines divergently selected for high and low FP were available. The FP observations were Box-Cox transformed, and FE and GLA observations were log and square root transformed, respectively. The estimated heritabilities of FE, GLA, and FP were 0.36, 0.29, and 0.20, respectively. The genetic correlation between FP and FE (GLA) was 0.17 (0.04). A high genetic correlation of 0.47 was estimated between FE and GLA. The recursive effect from FE to FP was [Formula: see text], and from GLA to FP [Formula: see text] These results imply that an increase of FE leads to an increased FP behavior and that an increase in GLA results in a higher FP value. Furthermore, the study showed that the genetic correlation among the traits is mainly caused by indirect effects. PMID:27252366

  12. Quantitative structure-activity relationships for fluoroelastomer/chlorofluorocarbon systems

    SciTech Connect

    Paciorek, K.J.L.; Masuda, S.R.; Nakahara, J.H. ); Snyder, C.E. Jr.; Warner, W.M. )

    1991-12-01

    This paper reports on swell, tensile, and modulus data that were determined for a fluoroelastomer after exposure to a series of chlorofluorocarbon model fluids. Quantitative structure-activity relationships (QSAR) were developed for the swell as a function of the number of carbons and chlorines and for tensile strength as a function of carbon number and chlorine positions in the chlorofluorocarbons.

  13. Structure-Activity Relationships in Nitro-Aromatic Compounds

    NASA Astrophysics Data System (ADS)

    Vogt, R. A.; Rahman, S.; Crespo-Hernández, C. E.

    Many nitro-aromatic compounds show mutagenic and carcinogenic properties, posing a potential human health risk. Despite this potential health hazard, nitro-aromatic compounds continue to be emitted into ambient air from municipal incinerators, motor vehicles, and industrial power plants. As a result, understanding the structural and electronic factors that influence mutagenicity in nitro-aromatic compounds has been a long standing objective. Progress toward this goal has accelerated over the years, in large part due to the synergistic efforts among toxicology, computational chemistry, and statistical modeling of toxicological data. The concerted influence of several structural and electronic factors in nitro-aromatic compounds makes the development of structure-activity relationships (SARs) a paramount challenge. Mathematical models that include a regression analysis show promise in predicting the mutagenic activity of nitro-aromatic compounds as well as in prioritizing compounds for which experimental data should be pursued. A major challenge of the structure-activity models developed thus far is their failure to apply beyond a subset of nitro-aromatic compounds. Most quantitative structure-activity relationship papers point to statistics as the most important confirmation of the validity of a model. However, the experimental evidence shows the importance of the chemical knowledge in the process of generating models with reasonable applicability. This chapter will concisely summarize the structural and electronic factors that influence the mutagenicity in nitro-aromatic compounds and the recent efforts to use quantitative structure-activity relationships to predict those physicochemical properties.

  14. Protective activity of (1S,2E,4R,6R,7E,11E)-2,7,11-cembratriene-4,6-diol analogues against diisopropylfluorophosphate neurotoxicity: preliminary structure-activity relationship and pharmacophore modeling.

    PubMed

    Eterović, Vesna A; Del Valle-Rodriguez, Angelie; Pérez, Dinely; Carrasco, Marimée; Khanfar, Mohammad A; El Sayed, Khalid A; Ferchmin, Pedro A

    2013-08-01

    Diisopropylfluorophosphate (DFP) is an organophosphorous insecticide used as a surrogate for the more toxic chemical warfare nerve agent sarin. DFP produces neurotoxicity in vivo and irreversibly decreases the area of population spikes recorded from the CA1 region of acute hippocampal slices. (1S,2E,4R,6R,7E,11E)-2,7,11-Cembratriene-4,6-diol (1) is a neuroprotective natural cembranoid that reverses DFP-induced damage both in vivo and in the hippocampal slice. Cembranoid 1 acts by noncompetitive inhibition of the α7 nicotinic acetylcholine receptor. This study aims at establishing a preliminary structure-activity relationship to define the neuroprotective cembranoid pharmacophores using the hippocampal slice assay and pharmacophore modeling. Fourteen natural, semisynthetic, or biocatalytic cembranoid analogues 2-15 related to 1 were tested for their capacity to protect the population spikes from DFP-induced damage and intrinsic toxicity. Twelve cembranoids caused significant reversal of DFP toxicity; only 3 active analogues displayed minor intrinsic toxicity at 10 μM. The C-4 epimer of 1 (2) and the 4-O-methyl ether analogue of 1 (3), were totally devoid of neuroprotective activity. The results suggested a model for cembranoid binding where the hydrophobic ring surface binds to a hydrophobic (Hbic) patch on the receptor molecule and an electronegative atom (oxygen or sulfur) in proper spatial relationship to the ring surface interacts with an electropositive group in the receptor binding site. A pharmacophore model consisting of 1 hydrogen bond acceptor (HBA), 2 Hbic, and 10 exclusion spheres was established using HipHop-REFINE and supported the above mentioned pharmacophoric hypothesis. PMID:23769165

  15. Protective activity of (1S,2E,4R,6R,7E,11E)-2,7,11-cembratriene-4,6-diol analogues against diisopropylfluorophosphate neurotoxicity: Preliminary structure-activity relationship and pharmacophore modeling

    PubMed Central

    Eterović, Vesna A.; Valle-Rodriguez, Angelie Del; Pérez, Dinely; Carrasco, Marimée; Khanfar, Mohammad A.; El Sayed, Khalid A.; Ferchmin, Pedro A.

    2013-01-01

    Diisopropylfluorophosphate (DFP) is an organophosphorous insecticide used as a surrogate for the more toxic chemical warfare nerve agent sarin. DFP produces neurotoxicity in vivo and irreversibly decreases the area of population spikes recorded from the CA1 region of acute hippocampal slices. (1S,2E,4R,6R,7E,11E)-2,7,11-Cembratriene-4,6-diol (1) is a neuroprotective natural cembranoid that reverses DFP-induced damage both in vivo and in the hippocampal slice. Cembranoid 1 acts by noncompetitive inhibition of the α7 nicotinic acetylcholine receptor. This study aims at establishing a preliminary structure-activity relationship to define the neuroprotective cembranoid pharmacophores using the hippocampal slice assay and pharmacophore modeling. Fourteen natural, semisyntheti or biocatalytic cembranoid analogues 2-15 related to 1 were tested for their capacity to protect the population spikes from DFP-induced damage and intrinsic toxicity. Twelve cembranoids caused significant reversal of DFP toxicity; only 3 active analogues displayed minor intrinsic toxicity at 10 μM. The C-4 epimer of 1 (2) and the 4-O-methyl ether analogue of 1 (3), were totally devoid of neuroprotective activity. The results suggested a model for cembranoid binding where the hydrophobic ring surface binds to a hydrophobic (Hbic) patch on the receptor molecule and an electronegative atom (oxygen or sulfur) in proper spatial relationship to the ring surface interacts with an electropositive group in the receptor binding site. A pharmacophore model consisting of 1 hydrogen bond acceptor (HBA), 2 Hbic, and 10 exclusion spheres was established using HipHop-REFINE and supported the above mentioned pharmacophoric hypothesis. PMID:23769165

  16. Protective activity of (1S,2E,4R,6R,7E,11E)-2,7,11-cembratriene-4,6-diol analogues against diisopropylfluorophosphate neurotoxicity: preliminary structure-activity relationship and pharmacophore modeling.

    PubMed

    Eterović, Vesna A; Del Valle-Rodriguez, Angelie; Pérez, Dinely; Carrasco, Marimée; Khanfar, Mohammad A; El Sayed, Khalid A; Ferchmin, Pedro A

    2013-08-01

    Diisopropylfluorophosphate (DFP) is an organophosphorous insecticide used as a surrogate for the more toxic chemical warfare nerve agent sarin. DFP produces neurotoxicity in vivo and irreversibly decreases the area of population spikes recorded from the CA1 region of acute hippocampal slices. (1S,2E,4R,6R,7E,11E)-2,7,11-Cembratriene-4,6-diol (1) is a neuroprotective natural cembranoid that reverses DFP-induced damage both in vivo and in the hippocampal slice. Cembranoid 1 acts by noncompetitive inhibition of the α7 nicotinic acetylcholine receptor. This study aims at establishing a preliminary structure-activity relationship to define the neuroprotective cembranoid pharmacophores using the hippocampal slice assay and pharmacophore modeling. Fourteen natural, semisynthetic, or biocatalytic cembranoid analogues 2-15 related to 1 were tested for their capacity to protect the population spikes from DFP-induced damage and intrinsic toxicity. Twelve cembranoids caused significant reversal of DFP toxicity; only 3 active analogues displayed minor intrinsic toxicity at 10 μM. The C-4 epimer of 1 (2) and the 4-O-methyl ether analogue of 1 (3), were totally devoid of neuroprotective activity. The results suggested a model for cembranoid binding where the hydrophobic ring surface binds to a hydrophobic (Hbic) patch on the receptor molecule and an electronegative atom (oxygen or sulfur) in proper spatial relationship to the ring surface interacts with an electropositive group in the receptor binding site. A pharmacophore model consisting of 1 hydrogen bond acceptor (HBA), 2 Hbic, and 10 exclusion spheres was established using HipHop-REFINE and supported the above mentioned pharmacophoric hypothesis.

  17. Evaluating a Model of Youth Physical Activity

    ERIC Educational Resources Information Center

    Heitzler, Carrie D.; Lytle, Leslie A.; Erickson, Darin J.; Barr-Anderson, Daheia; Sirard, John R.; Story, Mary

    2010-01-01

    Objective: To explore the relationship between social influences, self-efficacy, enjoyment, and barriers and physical activity. Methods: Structural equation modeling examined relationships between parent and peer support, parent physical activity, individual perceptions, and objectively measured physical activity using accelerometers among a…

  18. Modeling Spatial Relationships within a Fuzzy Framework.

    ERIC Educational Resources Information Center

    Petry, Frederick E.; Cobb, Maria A.

    1998-01-01

    Presents a model for representing and storing binary topological and directional relationships between 2-dimensional objects that is used to provide a basis for fuzzy querying capabilities. A data structure called an abstract spatial graph (ASG) is defined for the binary relationships that maintains all necessary information regarding topology and…

  19. Relationship between potential platelet activation and LCS

    NASA Astrophysics Data System (ADS)

    Shadden, Shawn

    2010-11-01

    In the study of blood flow, emphasis is often directed at understanding shear stress at the vessel wall due to its potentially disruptive influence on the endothelium. However, it is also known that shear stress has a potent effect on platelet activation. Platelet activation is a precursor for blood clotting, which in turn is the cause of most forms of death. Since most platelets are contained in the flow domain, it is important to consider stresses acting on the platelet as they are convected. Locations of high stress can correspond to boundaries between different dynamic regions and locations of hyperbolic points in the Eulerian sense. In the computation of LCS, strain in typically considered in the Lagrangian sense. In this talk we discuss the relationship between locations of potential platelet activation due to increased stress and locations of LCS marking increase Lagrangian deformation.

  20. Modelers and policymakers : improving the relationships.

    SciTech Connect

    Karas, Thomas H.

    2004-06-01

    On April 22 and 23, 2004, a diverse group of 14 policymakers, modelers, analysts, and scholars met with some 22 members of the Sandia National Laboratories staff to explores ways in which the relationships between modelers and policymakers in the energy and environment fields (with an emphasis on energy) could be made more productive for both. This report is not a transcription of that workshop, but draws very heavily on its proceedings. It first describes the concept of modeling, the varying ways in which models are used to support policymaking, and the institutional context for those uses. It then proposes that the goal of modelers and policymakers should be a relationship of mutual trust, built on a foundation of communication, supported by the twin pillars of policy relevance and technical credibility. The report suggests 20 guidelines to help modelers improve the relationship, followed by 10 guidelines to help policymakers toward the same goal.

  1. Peptide Bacteriocins--Structure Activity Relationships.

    PubMed

    Etayash, Hashem; Azmi, Sarfuddin; Dangeti, Ramana; Kaur, Kamaljit

    2015-01-01

    With the growing concerns in the scientific and health communities over increasing levels of antibiotic resistance, antimicrobial peptide bacteriocins have emerged as promising alternatives to conventional small molecule antibiotics. A substantial attention has recently focused on the utilization of bacteriocins in food preservation and health safety. Despite the fact that a large number of bacteriocins have been reported, only a few have been fully characterized and structurally elucidated. Since knowledge of the molecular structure is a key for understanding the mechanism of action and therapeutic effects of peptide, we centered our focus in this review on the structure-activity relationships of bacteriocins with a particular focus in seven bacteriocins, namely, nisin, microcin J25, microcin B17, microcin C, leucocin A, sakacin P, and pediocin PA-1. Significant structural changes responsible for the altered activity of the recent bacteriocin analogues are discussed here. PMID:26265354

  2. Obstacles to activity pacing: assessment, relationship to activity and functioning.

    PubMed

    Cane, Douglas; McCarthy, Mary; Mazmanian, Dwight

    2016-07-01

    Activity pacing is frequently included among the strategies provided to individuals with chronic pain to manage pain and improve functioning. Individuals with chronic pain may, however, limit their use of activity pacing because they perceive significant obstacles to its use. This study describes the development of a measure to assess obstacles to activity pacing and examines the relationship of this measure to activity patterns and functioning. A sample of 637 individuals with chronic pain completed items describing potential obstacles to activity pacing as part of their pretreatment assessment. Item analyses were used to construct a 14-item measure of obstacles to activity pacing. A subset of these individuals completed the measure again after completion of a group treatment program. The resulting measure demonstrated excellent internal consistency and was minimally affected by social desirability. Correlations with measures of activity and psychosocial functioning provided initial construct validity for the measure. Sex differences were found with women initially identifying more obstacles to activity pacing. Fewer obstacles were identified by both men and women after treatment, and these changes were related to modest changes in activity patterns and functioning. The present results identify a number of obstacles that may limit the use of activity pacing by individuals with chronic pain. Treatment may result in a decrease in the number of obstacles identified, and this change is related to changes in the individual's activity pattern and psychosocial functioning. PMID:26963845

  3. Mechanistic quantitative structure-activity relationship model for the photoinduced toxicity of polycyclic aromatic hydrocarbons. 2: An empirical model for the toxicity of 16 polycyclic aromatic hydrocarbons to the duckweed Lemna gibba L. G-3

    SciTech Connect

    Huang, X.D.; Krylov, S.N.; Ren, L.; McConkey, B.J.; Dixon, D.G.; Greenberg, B.M.

    1997-11-01

    Photoinduced toxicity of polycyclic aromatic hydrocarbons (PAHs) occurs via photosensitization reactions (e.g., generation of singlet-state oxygen) and by photomodification (photooxidation and/or photolysis) of the chemicals to more toxic species. The quantitative structure-activity relationship (QSAR) described in the companion paper predicted, in theory, that photosensitization and photomodification additively contribute to toxicity. To substantiate this QSAR modeling exercise it was necessary to show that toxicity can be described by empirically derived parameters. The toxicity of 16 PAHs to the duckweed Lemna gibba was measured as inhibition of leaf production in simulated solar radiation (a light source with a spectrum similar to that of sunlight). A predictive model for toxicity was generated based on the theoretical model developed in the companion paper. The photophysical descriptors required of each PAH for modeling were efficiency of photon absorbance, relative uptake, quantum yield for triplet-state formation, and the rate of photomodification. The photomodification rates of the PAHs showed a moderate correlation to toxicity, whereas a derived photosensitization factor (PSF; based on absorbance, triplet-state quantum yield, and uptake) for each PAH showed only a weak, complex correlation to toxicity. However, summing the rate of photomodification and the PSF resulted in a strong correlation to toxicity that had predictive value. When the PSF and a derived photomodification factor (PMF; based on the photomodification rate and toxicity of the photomodified PAHs) were summed, an excellent explanatory model of toxicity was produced, substantiating the additive contributions of the two factors.

  4. Use of quantitative shape-activity relationships to model the photoinduced toxicity of polycyclic aromatic hydrocarbons: Electron density shape features accurately predict toxicity

    SciTech Connect

    Mezey, P.G.; Zimpel, Z.; Warburton, P.; Walker, P.D.; Irvine, D.G.; Huang, X.D.; Dixon, D.G.; Greenberg, B.M.

    1998-07-01

    The quantitative shape-activity relationship (QShAR) methodology, based on accurate three-dimensional electron densities and detailed shape analysis methods, has been applied to a Lemna gibba photoinduced toxicity data set of 16 polycyclic aromatic hydrocarbon (PAH) molecules. In the first phase of the studies, a shape fragment QShAR database of PAHs was developed. The results provide a very good match to toxicity based on a combination of the local shape features of single rings in comparison to the central ring of anthracene and a more global shape feature involving larger molecular fragments. The local shape feature appears as a descriptor of the susceptibility of PAHs to photomodification and the global shape feature is probably related to photosensitization activity.

  5. Evaluating a Model of Youth Physical Activity

    PubMed Central

    Heitzler, Carrie D.; Lytle, Leslie A.; Erickson, Darin J.; Barr-Anderson, Daheia; Sirard, John R.; Story, Mary

    2011-01-01

    Objective To explore the relationship between social influences, self-efficacy, enjoyment, and barriers and physical activity. Methods Structural equation modeling examined relationships between parent and peer support, parent physical activity, individual perceptions, and objectively measured physical activity using accelerometers among a sample of youth aged 10–17 years (N=720). Results Peer support, parent physical activity, and perceived barriers were directly related to youth activity. The proposed model accounted for 14.7% of the variance in physical activity. Conclusions The results demonstrate a need to further explore additional individual, social, and environmental factors that may influence youth’s regular participation in physical activity. PMID:20524889

  6. A novel algorithm for QSAR (quantitative structure-activity relationships)

    SciTech Connect

    Carter, S. ); Nikolic, S.; Trinajstic, N. )

    1989-01-01

    A novel approach to quantitative structure-activity relationships (QSAR) is proposed. It is based on the molecular descriptor named the stereo-identification (SID) number. The applicability of this approach to QSAR studies is tested on aquatic toxicities of phenols against fathead minnows (Phimephales promelas). Our approach reproduced successfully the bioactivities of phenols and is superior to the Hall-Kier model based on Randic's connectivity index.

  7. Cationic phospholipids: structure transfection activity relationships

    SciTech Connect

    Koynova, Rumiana; Tenchov, Boris

    2010-01-18

    Synthetic cationic lipids are presently the most widely used non-viral gene carriers. Examined here is a particularly attractive cationic lipid class, triester phosphatidylcholines (PCs) exhibiting low toxicities and good transfection efficiency. Similarly to other cationic lipids, they form stable complexes (lipoplexes) with the polyanionic nucleic acids. A summary of studies on a set of {approx}30 cationic PCs reveals the existence of a strong, systematic dependence of their transfection efficiency on the lipid hydrocarbon chain structure: transfection activity increases with increase of chain unsaturation from 0 to 2 double bonds per lipid and decreases with increase of chain length in the range {approx}30-50 total number of chain carbon atoms. Maximum transfection was observed for ethyl phosphate PCs (EPCs) with monounsaturated 14:1 chains (total of 2 double bonds and 30 chain carbon atoms). Lipid phase behavior is known to depend strongly on the chain molecular structure and the above relationships thus substantiate a view that cationic PC phase propensities are an important determinant of their activity. Indeed, X-ray structural studies show that the rate of DNA release from lipoplexes as well as transfection activity well correlate with non-lamellar phase progressions observed in cationic PC mixtures with membrane lipids. These findings appear to be of considerable interest because, according to current views, key processes in lipid-mediated transfection such as lipoplex disassembly and DNA release within the cells are believed to take place upon cationic lipid mixing with cellular lipids.

  8. Pyrrolo[1,3]benzothiazepine-based serotonin and dopamine receptor antagonists. Molecular modeling, further structure-activity relationship studies, and identification of novel atypical antipsychotic agents.

    PubMed

    Campiani, Giuseppe; Butini, Stefania; Fattorusso, Caterina; Catalanotti, Bruno; Gemma, Sandra; Nacci, Vito; Morelli, Elena; Cagnotto, Alfredo; Mereghetti, Ilario; Mennini, Tiziana; Carli, Miriana; Minetti, Patrizia; Di Cesare, M Assunta; Mastroianni, Domenico; Scafetta, Nazzareno; Galletti, Bruno; Stasi, M Antonietta; Castorina, Massimo; Pacifici, Licia; Vertechy, Mario; Di Serio, Stefano; Ghirardi, Orlando; Tinti, Ornella; Carminati, Paolo

    2004-01-01

    Recently we reported the pharmacological characterization of the 9,10-dihydropyrrolo[1,3]benzothiazepine derivative (S)-(+)-8 as a novel atypical antipsychotic agent. This compound had an optimum pK(i) 5-HT(2A)/D(2) ratio of 1.21 (pK(i) 5-HT(2A) = 8.83; pK(i) D(2) = 7.79). The lower D(2) receptor affinity of (S)-(+)-8 compared to its enantiomer was explained by the difficulty in reaching the conformation required to optimally fulfill the D(2) pharmacophore. With the aim of finding novel atypical antipsychotics we further investigated the core structure of (S)-(+)-8, synthesizing analogues with specific substituents; the structure-activity relationship (SAR) study was also expanded with the design and synthesis of other analogues characterized by a pyrrolo[2,1-b][1,3]benzothiazepine skeleton, substituted on the benzo-fused ring or on the pyrrole system. On the 9,10-dihydro analogues the substituents introduced on the pyrrole ring were detrimental to affinity for dopamine and for 5-HT(2A) receptors, but the introduction of a double bond at C-9/10 on the structure of (S)-(+)-8 led to a potent D(2)/5-HT(2A) receptor ligand with a typical binding profile (9f, pK(i) 5-HT(2A)/D(2) ratio of 1.01, log Y = 8.43). Then, to reduce D(2) receptor affinity and restore atypicality on unsaturated analogues, we exploited the effect of specific substitutions on the tricyclic system of 9f. Through a molecular modeling approach we generated a novel series of potential atypical antipsychotic agents, with optimized 5HT(2A)/D(2) receptor affinity ratios and that were easier to synthesize and purify than the reference compound (S)-(+)-8. A number of SAR trends were identified, and among the analogues synthesized and tested in binding assays, 9d and 9m were identified as the most interesting, giving atypical log Y scores respectively 4.98 and 3.18 (pK(i) 5-HT(2A)/D(2) ratios of 1.20 and 1.30, respectively). They had a multireceptor affinity profile and could be promising atypical agents

  9. Inhibition of 2-Amino-1-methyl-6-phenylimidazo [4,5-b]pyridine (PhIP) Formation by Alkoxy Radical Scavenging of Flavonoids and Their Quantitative Structure-Activity Relationship in a Model System.

    PubMed

    Yu, Chundi; Shao, Zeping; Liu, Bing; Zhang, Yan; Wang, Shuo

    2016-08-01

    The inhibitory effect of 10 flavonoids on the formation of 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) in a creatinine-phenylalanine model system was investigated through electronic spin resonance and a quantitative structure-activity relationship. Alkoxy radicals were observed during the heating process, providing evidence for a radical pathway in the formation of PhIP. The alkoxy radical scavenging capability of the flavonoids was proportional to their inhibition of PhIP formation (IC50 ). We deduced that flavonoid inhibition of PhIP generation occurs via scavenging of alkoxy radicals during the heating process. Multiple linear regression and partial least squares models were used to elucidate the relationship between PhIP inhibition activity and structure characteristics of the flavonoids. The lipo-hydro partition coefficient and molecular fractional polar surface area of the flavonoids were found to be predictive of the inhibition effect.

  10. Inhibition of 2-Amino-1-methyl-6-phenylimidazo [4,5-b]pyridine (PhIP) Formation by Alkoxy Radical Scavenging of Flavonoids and Their Quantitative Structure-Activity Relationship in a Model System.

    PubMed

    Yu, Chundi; Shao, Zeping; Liu, Bing; Zhang, Yan; Wang, Shuo

    2016-08-01

    The inhibitory effect of 10 flavonoids on the formation of 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) in a creatinine-phenylalanine model system was investigated through electronic spin resonance and a quantitative structure-activity relationship. Alkoxy radicals were observed during the heating process, providing evidence for a radical pathway in the formation of PhIP. The alkoxy radical scavenging capability of the flavonoids was proportional to their inhibition of PhIP formation (IC50 ). We deduced that flavonoid inhibition of PhIP generation occurs via scavenging of alkoxy radicals during the heating process. Multiple linear regression and partial least squares models were used to elucidate the relationship between PhIP inhibition activity and structure characteristics of the flavonoids. The lipo-hydro partition coefficient and molecular fractional polar surface area of the flavonoids were found to be predictive of the inhibition effect. PMID:27384350

  11. Structure activity relationships of selected naphthalene derivatives

    SciTech Connect

    Schultz, T.W.; Dumont, J.N.; Sankey, F.D.; Schmoyer, R.L. Jr.

    1983-01-01

    Twenty-two derivatives of naphthalene were assayed under an acute static regime with biological activity being monitored as population growth of Tetrahymena pyriformis. Activity varied over one log unit. Substituent constant structure-activity analyses revealed the model, log BR = 0.282Ha + 0.352..pi.. + 0.692F + 0.334/sup 1/X/sub sub//sup v/ - 0.326R + 0.027, to be best and to account for 85% of the variation in log BR (BR, biological response; Ha, hydrogen acceptance; ..pi.., hydrophobic substituent constant; F, polar electronic substituent constant, /sup 1/X/sub sub//sup v/, substituent molar connectivity index; R, resonance electronic substituent constant). The Ha and ..pi.. parameters are the most important, accounting for 71% of the log BR variability. 21 references, 1 figure, 7 tables.

  12. Quantitative Structure-Antifungal Activity Relationships for cinnamate derivatives.

    PubMed

    Saavedra, Laura M; Ruiz, Diego; Romanelli, Gustavo P; Duchowicz, Pablo R

    2015-12-01

    Quantitative Structure-Activity Relationships (QSAR) are established with the aim of analyzing the fungicidal activities of a set of 27 active cinnamate derivatives. The exploration of more than a thousand of constitutional, topological, geometrical and electronic molecular descriptors, which are calculated with Dragon software, leads to predictions of the growth inhibition on Pythium sp and Corticium rolfsii fungi species, in close agreement to the experimental values extracted from the literature. A set containing 21 new structurally related cinnamate compounds is prepared. The developed QSAR models are applied to predict the unknown fungicidal activity of this set, showing that cinnamates like 38, 28 and 42 are expected to be highly active for Pythium sp, while this is also predicted for 28 and 34 in C. rolfsii. PMID:26410195

  13. Probabilistic hazard assessment for skin sensitization potency by dose–response modeling using feature elimination instead of quantitative structure–activity relationships

    PubMed Central

    McKim, James M.; Hartung, Thomas; Kleensang, Andre; Sá-Rocha, Vanessa

    2016-01-01

    Supervised learning methods promise to improve integrated testing strategies (ITS), but must be adjusted to handle high dimensionality and dose–response data. ITS approaches are currently fueled by the increasing mechanistic understanding of adverse outcome pathways (AOP) and the development of tests reflecting these mechanisms. Simple approaches to combine skin sensitization data sets, such as weight of evidence, fail due to problems in information redundancy and high dimension-ality. The problem is further amplified when potency information (dose/response) of hazards would be estimated. Skin sensitization currently serves as the foster child for AOP and ITS development, as legislative pressures combined with a very good mechanistic understanding of contact dermatitis have led to test development and relatively large high-quality data sets. We curated such a data set and combined a recursive variable selection algorithm to evaluate the information available through in silico, in chemico and in vitro assays. Chemical similarity alone could not cluster chemicals’ potency, and in vitro models consistently ranked high in recursive feature elimination. This allows reducing the number of tests included in an ITS. Next, we analyzed with a hidden Markov model that takes advantage of an intrinsic inter-relationship among the local lymph node assay classes, i.e. the monotonous connection between local lymph node assay and dose. The dose-informed random forest/hidden Markov model was superior to the dose-naive random forest model on all data sets. Although balanced accuracy improvement may seem small, this obscures the actual improvement in misclassifications as the dose-informed hidden Markov model strongly reduced "false-negatives" (i.e. extreme sensitizers as non-sensitizer) on all data sets. PMID:26046447

  14. A Generic Model of Dyadic Social Relationships

    PubMed Central

    Favre, Maroussia; Sornette, Didier

    2015-01-01

    We introduce a model of dyadic social interactions and establish its correspondence with relational models theory (RMT), a theory of human social relationships. RMT posits four elementary models of relationships governing human interactions, singly or in combination: Communal Sharing, Authority Ranking, Equality Matching, and Market Pricing. To these are added the limiting cases of asocial and null interactions, whereby people do not coordinate with reference to any shared principle. Our model is rooted in the observation that each individual in a dyadic interaction can do either the same thing as the other individual, a different thing or nothing at all. To represent these three possibilities, we consider two individuals that can each act in one out of three ways toward the other: perform a social action X or Y, or alternatively do nothing. We demonstrate that the relationships generated by this model aggregate into six exhaustive and disjoint categories. We propose that four of these categories match the four relational models, while the remaining two correspond to the asocial and null interactions defined in RMT. We generalize our results to the presence of N social actions. We infer that the four relational models form an exhaustive set of all possible dyadic relationships based on social coordination. Hence, we contribute to RMT by offering an answer to the question of why there could exist just four relational models. In addition, we discuss how to use our representation to analyze data sets of dyadic social interactions, and how social actions may be valued and matched by the agents. PMID:25826403

  15. Friend Flips: A Story Activity about Relationships

    ERIC Educational Resources Information Center

    Szucs, Leigh; Reyes, Jovanni V.; Farmer, Jennifer; Wilson, Kelly L.; McNeill, Elisa Beth

    2015-01-01

    Adolescents are influenced by the type, length and quality of the connections shared with different people throughout their lifespan. Relationships with peers, friends, and adults help to shape knowledge, attitudes, and beliefs related to health. Recognizing healthy or unhealthy characteristics allow youth to strengthen relationships and…

  16. Brief Report: Activities in Heterosexual Romantic Relationships--Grade Differences and Associations with Relationship Satisfaction

    ERIC Educational Resources Information Center

    Carlson, Wendy; Rose, Amanda J.

    2012-01-01

    Whereas much research addresses relations of youths' heterosexual romantic relationships with sexual and/or delinquent activities, less attention has been paid to youths' more normative, day-to-day activities with romantic partners. This gap in the literature is problematic given that these activities define the substance of the relationships and…

  17. Structure-Activity Relationships and Pharmacophore Model of a Non-Competitive Pyrazoline Containing Class of GluN2C/GluN2D Selective Antagonists

    PubMed Central

    Acker, Timothy M.; Khatri, Alpa; Vance, Katie M.; Slabber, Cathryn; Bacsa, John; Snyder, James P.; Traynelis, Stephen F.; Liotta, Dennis C.

    2013-01-01

    Here we describe the synthesis and structure-activity relationship for a class of pyrazoline-containing dihydroquinolone negative allosteric modulators of the NMDA receptor that show strong subunit-selectivity for GluN2C- and GluN2D-containing receptors over GluN2A-and GluN2B-containing receptors. Several members of this class inhibit NMDA receptor responses in the nanomolar range, and are more than 50-fold selective over GluN1/GluN2A and GluN1/GluN2B NMDA receptors, as well as AMPA, kainate, GABA, glycine, nicotinic, serotonin, and purinergic receptors. Analysis of the purified enantiomers of one of the more potent and selective compounds shows that the S-enantiomer is both more potent and more selective than the R-enantiomer. The S-enantiomer had an IC50 value of 0.17–0.22 µM at GluN2D- and GluN2C-containing receptors, respectively, and showed over 70-fold selectivity over other NMDA receptor subunits. The subunit-selectivity of this class of compounds should be useful in defining the role of GluN2C- and GluN2D-containing receptors in specific brain circuits in both physiological and patho-physiological conditions. PMID:23909910

  18. Complementary three-dimensional quantitative structure-activity relationship modeling of binding affinity and functional potency: a study on alpha4beta2 nicotinic ligands.

    PubMed

    Tosco, Paolo; Ahring, Philip K; Dyhring, Tino; Peters, Dan; Harpsøe, Kasper; Liljefors, Tommy; Balle, Thomas

    2009-04-23

    Complementary 3D-QSAR modeling of binding affinity and functional potency is proposed as a tool to pinpoint the molecular features of the ligands, and the corresponding amino acids in the receptor, responsible for high affinity binding vs those driving agonist behavior and receptor activation. This approach proved successful on a series of nicotinic alpha(4)beta(2) ligands, whose partial/full agonist profile could be linked to the size of the scaffold as well as to the nature of the substituents.

  19. Structure-activity relationship studies of pyrrolone antimalarial agents.

    PubMed

    Murugesan, Dinakaran; Kaiser, Marcel; White, Karen L; Norval, Suzanne; Riley, Jennifer; Wyatt, Paul G; Charman, Susan A; Read, Kevin D; Yeates, Clive; Gilbert, Ian H

    2013-09-01

    Previously reported pyrrolones, such as TDR32570, exhibited potential as antimalarial agents; however, while these compounds have potent antimalarial activity, they suffer from poor aqueous solubility and metabolic instability. Here, further structure-activity relationship studies are described that aimed to solve the developability issues associated with this series of compounds. In particular, further modifications to the lead pyrrolone, involving replacement of a phenyl ring with a piperidine and removal of a potentially metabolically labile ester by a scaffold hop, gave rise to derivatives with improved in vitro antimalarial activities against Plasmodium falciparum K1, a chloroquine- and pyrimethamine-resistant parasite strain, with some derivatives exhibiting good selectivity for parasite over mammalian (L6) cells. Three representative compounds were selected for evaluation in a rodent model of malaria infection, and the best compound showed improved ability to decrease parasitaemia and a slight increase in survival.

  20. A Novel Pyrazolopyridine with in Vivo Activity in Plasmodium berghei- and Plasmodium falciparum-Infected Mouse Models from Structure-Activity Relationship Studies around the Core of Recently Identified Antimalarial Imidazopyridazines.

    PubMed

    Le Manach, Claire; Paquet, Tanya; Brunschwig, Christel; Njoroge, Mathew; Han, Ze; Gonzàlez Cabrera, Diego; Bashyam, Sridevi; Dhinakaran, Rajkumar; Taylor, Dale; Reader, Janette; Botha, Mariette; Churchyard, Alisje; Lauterbach, Sonja; Coetzer, Theresa L; Birkholtz, Lyn-Marie; Meister, Stephan; Winzeler, Elizabeth A; Waterson, David; Witty, Michael J; Wittlin, Sergio; Jiménez-Díaz, María-Belén; Santos Martínez, María; Ferrer, Santiago; Angulo-Barturen, Iñigo; Street, Leslie J; Chibale, Kelly

    2015-11-12

    Toward improving pharmacokinetics, in vivo efficacy, and selectivity over hERG, structure-activity relationship studies around the central core of antimalarial imidazopyridazines were conducted. This study led to the identification of potent pyrazolopyridines, which showed good in vivo efficacy and pharmacokinetics profiles. The lead compounds also proved to be very potent in the parasite liver and gametocyte stages, which makes them of high interest. PMID:26502160

  1. Relationships between coordination, active drag and propelling efficiency in crawl.

    PubMed

    Seifert, Ludovic; Schnitzler, Christophe; Bideault, Gautier; Alberty, Morgan; Chollet, Didier; Toussaint, Huub Martin

    2015-02-01

    This study examines the relationships between the index of coordination (IdC) and active drag (D) assuming that at constant average speed, average drag equals average propulsion. The relationship between IdC and propulsive efficiency (ep) was also investigated at maximal speed. Twenty national swimmers completed two incremental speed tests swimming front crawl with arms only in free condition and using a measurement of active drag system. Each test was composed of eight 25-m bouts from 60% to 100% of maximal intensity whereby each lap was swum at constant speed. Different regression models were tested to analyse IdC-D relationship. Correlation between IdC and ep was calculated. IdC was linked to D by linear regression (IdC=0.246·D-27.06; R(2)=0.88, P<.05); swimmers switched from catch-up to superposition coordination mode at a speed of ∼1.55ms(-1) where average D is ∼110N. No correlation between IdC and ep at maximal speed was found. The intra-individual analysis revealed that coordination plays an important role in scaling propulsive forces with higher speed levels such that these are adapted to aquatic resistance. Inter-individual analysis showed that high IdC did not relate to a high ep suggesting an individual optimization of force and power generation is at play to reach high speeds.

  2. Prediction of activated carbon adsorption capacities for organic vapors using quantitative structure-activity relationship methods

    SciTech Connect

    Nirmalakhandan, N.N. ); Speece, R.E. )

    1993-08-01

    Quantitative structure-activity relationship (QSAR) methods were used to develop models to estimate and predict activated carbon adsorption capacities for organic vapors. Literature isothermal data from two sources for 22 organic contaminants on six different carbons were merged to form a training set of 75 data points. Two different QSAR approaches were evaluated: the molecular connectivity approach and the linear solvation energy relationship approach. The QSAR model developed in this study using the molecular connectivity approach was able to fit the experimental data with r = 0.96 and standard error of 0.09. The utility of the model was demonstrated by using predicted k values to calculate adsorption capacities of 12 chemicals on two different carbons and comparing them with experimentally determined values. 9 refs., 1 fig., 3 tabs.

  3. Research Data Management and Libraries: Relationships, Activities, Drivers and Influences

    PubMed Central

    Pinfield, Stephen; Cox, Andrew M.; Smith, Jen

    2014-01-01

    The management of research data is now a major challenge for research organisations. Vast quantities of born-digital data are being produced in a wide variety of forms at a rapid rate in universities. This paper analyses the contribution of academic libraries to research data management (RDM) in the wider institutional context. In particular it: examines the roles and relationships involved in RDM, identifies the main components of an RDM programme, evaluates the major drivers for RDM activities, and analyses the key factors influencing the shape of RDM developments. The study is written from the perspective of library professionals, analysing data from 26 semi-structured interviews of library staff from different UK institutions. This is an early qualitative contribution to the topic complementing existing quantitative and case study approaches. Results show that although libraries are playing a significant role in RDM, there is uncertainty and variation in the relationship with other stakeholders such as IT services and research support offices. Current emphases in RDM programmes are on developments of policies and guidelines, with some early work on technology infrastructures and support services. Drivers for developments include storage, security, quality, compliance, preservation, and sharing with libraries associated most closely with the last three. The paper also highlights a ‘jurisdictional’ driver in which libraries are claiming a role in this space. A wide range of factors, including governance, resourcing and skills, are identified as influencing ongoing developments. From the analysis, a model is constructed designed to capture the main aspects of an institutional RDM programme. This model helps to clarify the different issues involved in RDM, identifying layers of activity, multiple stakeholders and drivers, and a large number of factors influencing the implementation of any initiative. Institutions may usefully benchmark their activities against

  4. Research data management and libraries: relationships, activities, drivers and influences.

    PubMed

    Pinfield, Stephen; Cox, Andrew M; Smith, Jen

    2014-01-01

    The management of research data is now a major challenge for research organisations. Vast quantities of born-digital data are being produced in a wide variety of forms at a rapid rate in universities. This paper analyses the contribution of academic libraries to research data management (RDM) in the wider institutional context. In particular it: examines the roles and relationships involved in RDM, identifies the main components of an RDM programme, evaluates the major drivers for RDM activities, and analyses the key factors influencing the shape of RDM developments. The study is written from the perspective of library professionals, analysing data from 26 semi-structured interviews of library staff from different UK institutions. This is an early qualitative contribution to the topic complementing existing quantitative and case study approaches. Results show that although libraries are playing a significant role in RDM, there is uncertainty and variation in the relationship with other stakeholders such as IT services and research support offices. Current emphases in RDM programmes are on developments of policies and guidelines, with some early work on technology infrastructures and support services. Drivers for developments include storage, security, quality, compliance, preservation, and sharing with libraries associated most closely with the last three. The paper also highlights a 'jurisdictional' driver in which libraries are claiming a role in this space. A wide range of factors, including governance, resourcing and skills, are identified as influencing ongoing developments. From the analysis, a model is constructed designed to capture the main aspects of an institutional RDM programme. This model helps to clarify the different issues involved in RDM, identifying layers of activity, multiple stakeholders and drivers, and a large number of factors influencing the implementation of any initiative. Institutions may usefully benchmark their activities against the

  5. Research data management and libraries: relationships, activities, drivers and influences.

    PubMed

    Pinfield, Stephen; Cox, Andrew M; Smith, Jen

    2014-01-01

    The management of research data is now a major challenge for research organisations. Vast quantities of born-digital data are being produced in a wide variety of forms at a rapid rate in universities. This paper analyses the contribution of academic libraries to research data management (RDM) in the wider institutional context. In particular it: examines the roles and relationships involved in RDM, identifies the main components of an RDM programme, evaluates the major drivers for RDM activities, and analyses the key factors influencing the shape of RDM developments. The study is written from the perspective of library professionals, analysing data from 26 semi-structured interviews of library staff from different UK institutions. This is an early qualitative contribution to the topic complementing existing quantitative and case study approaches. Results show that although libraries are playing a significant role in RDM, there is uncertainty and variation in the relationship with other stakeholders such as IT services and research support offices. Current emphases in RDM programmes are on developments of policies and guidelines, with some early work on technology infrastructures and support services. Drivers for developments include storage, security, quality, compliance, preservation, and sharing with libraries associated most closely with the last three. The paper also highlights a 'jurisdictional' driver in which libraries are claiming a role in this space. A wide range of factors, including governance, resourcing and skills, are identified as influencing ongoing developments. From the analysis, a model is constructed designed to capture the main aspects of an institutional RDM programme. This model helps to clarify the different issues involved in RDM, identifying layers of activity, multiple stakeholders and drivers, and a large number of factors influencing the implementation of any initiative. Institutions may usefully benchmark their activities against the

  6. Supervisor's Interactive Model of Organizational Relationships

    ERIC Educational Resources Information Center

    O'Reilly, Frances L.; Matt, John; McCaw, William P.

    2014-01-01

    The Supervisor's Interactive Model of Organizational Relationships (SIMOR) integrates two models addressed in the leadership literature and then highlights the importance of relationships. The Supervisor's Interactive Model of Organizational Relationships combines the modified Hersey and Blanchard model of situational leadership, the…

  7. Conformation-Activity Relationships of Polyketide Natural Products

    PubMed Central

    Larsen, Erik M.; Wilson, Matthew R.; Taylor, Richard E.

    2015-01-01

    Polyketides represent an important class of secondary metabolites that interact with biological targets connected to a variety of disease-associated pathways. Remarkably, nature’s assembly lines, polyketide synthases, manufacture these privileged structures through a combinatorial mixture of just a few structural units. This review highlights the role of these structural elements in shaping a polyketide’s conformational preferences, the use of computer-based molecular modeling and solution NMR studies in the identification of low-energy conformers, and the importance of conformational analogues in probing the bound conformation. In particular, this review covers several examples wherein conformational analysis complements classic structure-activity relationships in the design of biologically active natural product analogues. PMID:25974024

  8. The Relationships Between Modelling and Argumentation from the Perspective of the Model of Modelling Diagram

    NASA Astrophysics Data System (ADS)

    Cardoso Mendonça, Paula Cristina; Justi, Rosária

    2013-09-01

    Some studies related to the nature of scientific knowledge demonstrate that modelling is an inherently argumentative process. This study aims at discussing the relationship between modelling and argumentation by analysing data collected during the modelling-based teaching of ionic bonding and intermolecular interactions. The teaching activities were planned from the transposition of the main modelling stages that constitute the 'Model of Modelling Diagram' so that students could experience each of such stages. All the lessons were video recorded and their transcriptions supported the elaboration of case studies for each group of students. From the analysis of the case studies, we identified argumentative situations when students performed all of the modelling stages. Our data show that the argumentative situations were related to sense making, articulating and persuasion purposes, and were closely related to the generation of explanations in the modelling processes. They also show that representations are important resources for argumentation. Our results are consistent with some of those already reported in the literature regarding the relationship between modelling and argumentation, but are also divergent when they show that argumentation is not only related to the model evaluation phase.

  9. The relationship between chitotriosidase activity and tuberculosis.

    PubMed

    Chen, M; Deng, J; Li, W; Su, C; Xia, Y; Wang, M; Li, X; Abuaku, B K; Tan, H; Wen, S W

    2015-11-01

    Chitotriosidase, secreted by activated macrophages, is a biomarker of activated macrophages. In this study, we explored whether chitotriosidase could be adopted as a biomarker to evaluate the curative effect on tuberculosis (TB). Five counties were randomly selected out of 122 counties/cities/districts in Hunan Province, China. Our cases were all TB patients who were newly diagnosed or had been receiving treatment at the Centers for Disease Control (CDCs) of these five counties between April and August in 2009. Healthy controls were selected from a community health facility in the Kaifu district of Changsha City after frequency-matching of gender and age with the cases. Chitotriosidase activity was evaluated by a fluorometric assay. Categorical variables were analysed with the χ 2 test. Measurement data in multiple groups were tested with analysis of variance and least significant difference (LSD). Correlation between chitotriosidase activity and the degree of radiological extent (DRE) was examined by Spearman's rank correlation test. The average chitotriosidase activity levels of new TB cases, TB cases with different periods of treatment (6 months) and the control group were 54·47, 34·77, 21·54, 12·73 and 10·53 nmol/h.ml, respectively. Chitotriosidase activity in TB patients declined along with the continuity of treatment. The chitotriosidase activity of both smear-positive and the smear-negative pulmonary TB patients decreased after 6 months' treatment to normal levels (P < 0·05). Moreover, chitotriosidase activity was positively correlated with DRE (r = 0·607, P < 0·001). Our results indicate that chitotriosidase might be a marker of TB treatment effects. However, further follow-up study of TB patients is needed in the future. PMID:26418349

  10. Structure activity relationships: their function in biological prediction

    SciTech Connect

    Schultz, T.W.

    1982-01-01

    Quantitative structure activity relationships provide a means of ranking or predicting biological effects based on chemical structure. For each compound used to formulate a structure activity model two kinds of quantitative information are required: (1) biological activity and (2) molecular properties. Molecular properties are of three types: (1) molecular shape, (2) physiochemical parameters, and (3) abstract quantitations of molecular structure. Currently the two best descriptors are the hydrophobic parameter, log 1-octanol/water partition coefficient (log P), and the /sup 1/X/sup v/(one-chi-v) molecular connectivity index. Biological responses can be divided into three main categories: (1) non-specific effects due to membrane perturbation, (2) non-specific effects due to interaction with functional groups of proteins, and (3) specific effects due to interaction with receptors. Twenty-six synthetic fossil fuel-related nitrogen-containing aromatic compounds were examined to determine the quantitative correlation between log P and /sup 1/X/sup v/ and population growth impairment of Tetrahymena pyriformis. Nitro-containing compounds are the most active, followed by amino-containing compounds and azaarenes. Within each analog series activity increases with alkyl substitution and ring addition. The planar model log BR = 0.5564 log P + 0.3000 /sup 1/X/sup v/ -2.0138 was determined using mono-nitrogen substituted compounds. Attempts to extrapolate this model to dinitrogen-containing molecules were, for the most part, unsuccessful because of a change in mode of action from membrane perturbation to uncoupling of oxidative phosphoralation.

  11. Structure-activity relationship of cyanine tau aggregation inhibitors

    PubMed Central

    Chang, Edward; Congdon, Erin E.; Honson, Nicolette S.; Duff, Karen E.; Kuret, Jeff

    2009-01-01

    A structure-activity relationship for symmetrical cyanine inhibitors of human tau aggregation was elaborated using a filter trap assay. Antagonist activity depended on cyanine heterocycle, polymethine bridge length, and the nature of meso- and N-substituents. One potent member of the series, 3,3’-diethyl-9-methylthiacarbocyanine iodide (compound 11), retained submicromolar potency and had calculated physical properties consistent with blood-brain barrier and cell membrane penetration. Exposure of organotypic slices prepared from JNPL3 transgenic mice (which express human tau harboring the aggregation prone P301L tauopathy mutation) to compound 11 for one week revealed a biphasic dose response relationship. Low nanomolar concentrations decreased insoluble tau aggregates to half those observed in slices treated with vehicle alone. In contrast, high concentrations (≥300 nM) augmented tau aggregation and produced abnormalities in tissue tubulin levels. These data suggest that certain symmetrical carbocyanine dyes can modulate tau aggregation in the slice biological model at concentrations well below those associated with toxicity. PMID:19432420

  12. Possible relationships between solar activity and meteorological phenomena

    NASA Technical Reports Server (NTRS)

    Bandeen, W. R. (Editor); Maran, S. P. (Editor)

    1975-01-01

    A symposium was conducted in which the following questions were discussed: (1) the evidence concerning possible relationships between solar activity and meteorological phenomena; (2) plausible physical mechanisms to explain these relationships; and (3) kinds of critical measurements needed to determine the nature of solar/meteorological relationships and/or the mechanisms to explain them, and which of these measurements can be accomplished best from space.

  13. Active Ageing: Intergenerational Relationships and Social Generativity.

    PubMed

    Rossi, Giovanna; Boccacin, Lucia; Bramanti, Donatella; Meda, Stefania G

    2014-01-01

    This contribution is a reflection on the concept of active ageing from the perspective of relational sociology. At the same time, it offers practical implications and outlines possible future courses of action, in the face of demographic and relational scenarios rapidly changing, and the challenges that each day people of all generations are called to cope with. Active ageing is quite a recent concept and indicates an attitude towards ageing that enhances the quality of life as people become older. The goal of active ageing is to enable people to realise their potential for physical, social and mental well-being and to participate in social life also in the last stage of the life cycle. In this phase, the presence of a network of support, security and care adequate to the possible onset of problems and criticalities is crucial. Relational sociology frames the phenomenon of an ageing population in a dense network of social relations, primarily at the level of family and community. For this reason, as supported by the most recent sociological literature and evidence from studies conducted in Italy and abroad (cf. SHARE), it is extremely important to investigate the link between active ageing, intergenerational orientation (solidarity and exchanges) and practices of prosociality (i.e. engagement in third-sector activities and volunteering in later life).

  14. Attachment relationships and physical activity motivation of college students.

    PubMed

    Ullrich-French, Sarah; Smith, Alan L; Cox, Anne E

    2011-08-01

    This study was designed to assess the link of attachment relationships with physical activity motivation. Potential mediators of this link were examined in a cross-sectional study targeting college student physical activity motivation and behaviour. Participants completed self-reports of attachment relationships (with mother, father and best friend), self-determined motivation for physical activity, physical activity behaviour and the hypothesised mediator variables of perceived competence, autonomy and relatedness. The results provide support for the mediating role of these variables in the association of father attachment with self-determined motivation. Meaningful variance in self-determined motivation for physical activity and physical activity behaviour was explained. Overall, attachment relationships appear to be relevant, albeit modestly, to physical activity motivation of college students. The findings support continued efforts to integrate attachment and motivational perspectives in the study of college student health behaviour.

  15. Anti-AIDS agents 79. Design, synthesis, molecular modeling and structure-activity relationships of novel dicamphanoyl-2',2'-dimethyldihydropyranochromone (DCP) analogs as potent anti-HIV agents.

    PubMed

    Zhou, Ting; Shi, Qian; Chen, Chin-Ho; Zhu, Hao; Huang, Li; Ho, Phong; Lee, Kuo-Hsiung

    2010-09-15

    In a continued study, 23 3'R,4'R-di-O-(-)-camphanoyl-2',2'-dimethyldihydropyrano[2,3-f]chromone (DCP) derivatives (5-27) were synthesized, and screened for anti-HIV activity against both a non-drug-resistant NL4-3 strain and multiple reverse transcriptase (RT) inhibitor-resistant (RTMDR-1) strain, using 2-EDCP (4) and 2-MDCP (35) as controls. New DCP analogs 5, 9, 14, and 22 exhibited potent anti-HIV activity against HIVNL4-3 with EC50 and therapeutic index (TI) values ranging from 0.036 microM to 0.14 microM and from 110 to 420, respectively. Compounds 5 and 9 also exhibited good activity against RTMDR-1 (EC50 0.049 and 0.054 microM; TI 310 and 200, respectively), and were twofold more potent than the leads 4 and 35 (EC50 0.11 and 0.19 microM; TI 60 and 58, respectively). Evaluation of water solubility showed that 5 and 22 were 5-10 times more water soluble than 4. Quantitative structure-activity relationship (QSAR) modeling results were first performed on this compound type, and the models should aid in design of future anti-HIV DCP analogs and potential clinical drug candidates.

  16. Synthesis, biological activities, and quantitative structure-activity relationship (QSAR) study of novel camptothecin analogues.

    PubMed

    Wu, Dan; Zhang, Shao-Yong; Liu, Ying-Qian; Wu, Xiao-Bing; Zhu, Gao-Xiang; Zhang, Yan; Wei, Wei; Liu, Huan-Xiang; Chen, An-Liang

    2015-05-13

    In continuation of our program aimed at the development of natural product-based pesticidal agents, three series of novel camptothecin derivatives were designed, synthesized, and evaluated for their biological activities against T. Cinnabarinus, B. brassicae, and B. xylophilus. All of the derivatives showed good-to-excellent activity against three insect species tested, with LC50 values ranging from 0.00761 to 0.35496 mmol/L. Remarkably, all of the compounds were more potent than CPT against T. Cinnabarinus, and compounds 4d and 4c displayed superior activity (LC50 0.00761 mmol/L and 0.00942 mmol/L, respectively) compared with CPT (LC50 0.19719 mmol/L) against T. Cinnabarinus. Based on the observed bioactivities, preliminary structure-activity relationship (SAR) correlations were also discussed. Furthermore, a three-dimensional quantitative structure-activity relationship (3D-QSAR) model using comparative molecular field analysis (CoMFA) was built. The model gave statistically significant results with the cross-validated q2 values of 0.580 and correlation coefficient r2 of 0.991 and  of 0.993. The QSAR analysis indicated that the size of the substituents play an important in the activity of 7-modified camptothecin derivatives. These findings will pave the way for further design, structural optimization, and development of camptothecin-derived compounds as pesticidal agents.

  17. Young Adolescents' Perceptions of Romantic Relationships and Sexual Activity

    ERIC Educational Resources Information Center

    Royer, Heather R.; Keller, Mary L.; Heidrich, Susan M.

    2009-01-01

    The purpose of this article is to describe young adolescents' perceptions of romantic relationships, ratings of important romantic partner characteristics, and acceptability of sexual activity with romantic relationships. Fifty-seven eighth-grade participants (average age = 13.8 years) from one urban US public middle school completed an anonymous…

  18. Relationships between Reading Activities and Language Use.

    ERIC Educational Resources Information Center

    Gordon, Sandra L.; Van Dongen, Richard

    1988-01-01

    Noting that the ways children encounter and use print in the classroom can be examined as surface and organizing content of curriculum, this article provides descriptions of innovative uses of print in the kindergarten and elementary school classroom. Curriculum "surface content" includes activities, use of classroom space, display, and materials…

  19. Relationships between Interlibrary Loan and Research Activity in Canada

    ERIC Educational Resources Information Center

    Duy, Joanna; Larivière, Vincent

    2014-01-01

    Interlibrary Loan borrowing rates in academic libraries are influenced by an array of factors. This article explores the relationship between interlibrary loan borrowing activity and research activity at 42 Canadian academic institutions. A significant positive correlation was found between interlibrary loan borrowing activity and measures of…

  20. Antiproliferative and Structure Activity Relationships of Amaryllidaceae Alkaloids.

    PubMed

    Cedrón, Juan C; Ravelo, Ángel G; León, Leticia G; Padrón, José M; Estévez-Braun, Ana

    2015-07-30

    The antiproliferative activity of a set of seven natural Amaryllidaceae alkaloids and 32 derivatives against four cancer cell lines (A2780, SW1573, T47-D and WiDr) was determined. The best antiproliferative activities were achieved with alkaloids derived from pancracine (2), haemanthamine (6) and haemantidine (7). For each skeleton, some structure-activity relationships were outlined.

  1. Active shape models unleashed

    NASA Astrophysics Data System (ADS)

    Kirschner, Matthias; Wesarg, Stefan

    2011-03-01

    Active Shape Models (ASMs) are a popular family of segmentation algorithms which combine local appearance models for boundary detection with a statistical shape model (SSM). They are especially popular in medical imaging due to their ability for fast and accurate segmentation of anatomical structures even in large and noisy 3D images. A well-known limitation of ASMs is that the shape constraints are over-restrictive, because the segmentations are bounded by the Principal Component Analysis (PCA) subspace learned from the training data. To overcome this limitation, we propose a new energy minimization approach which combines an external image energy with an internal shape model energy. Our shape energy uses the Distance From Feature Space (DFFS) concept to allow deviations from the PCA subspace in a theoretically sound and computationally fast way. In contrast to previous approaches, our model does not rely on post-processing with constrained free-form deformation or additional complex local energy models. In addition to the energy minimization approach, we propose a new method for liver detection, a new method for initializing an SSM and an improved k-Nearest Neighbour (kNN)-classifier for boundary detection. Our ASM is evaluated with leave-one-out tests on a data set with 34 tomographic CT scans of the liver and is compared to an ASM with standard shape constraints. The quantitative results of our experiments show that we achieve higher segmentation accuracy with our energy minimization approach than with standard shape constraints.nym

  2. Quantitative structure-activity relationships for organophosphates binding to acetylcholinesterase.

    PubMed

    Ruark, Christopher D; Hack, C Eric; Robinson, Peter J; Anderson, Paul E; Gearhart, Jeffery M

    2013-02-01

    Organophosphates are a group of pesticides and chemical warfare nerve agents that inhibit acetylcholinesterase, the enzyme responsible for hydrolysis of the excitatory neurotransmitter acetylcholine. Numerous structural variants exist for this chemical class, and data regarding their toxicity can be difficult to obtain in a timely fashion. At the same time, their use as pesticides and military weapons is widespread, which presents a major concern and challenge in evaluating human toxicity. To address this concern, a quantitative structure-activity relationship (QSAR) was developed to predict pentavalent organophosphate oxon human acetylcholinesterase bimolecular rate constants. A database of 278 three-dimensional structures and their bimolecular rates was developed from 15 peer-reviewed publications. A database of simplified molecular input line entry notations and their respective acetylcholinesterase bimolecular rate constants are listed in Supplementary Material, Table I. The database was quite diverse, spanning 7 log units of activity. In order to describe their structure, 675 molecular descriptors were calculated using AMPAC 8.0 and CODESSA 2.7.10. Orthogonal projection to latent structures regression, bootstrap leave-random-many-out cross-validation and y-randomization were used to develop an externally validated consensus QSAR model. The domain of applicability was assessed by the William's plot. Six external compounds were outside the warning leverage indicating potential model extrapolation. A number of compounds had residuals >2 or <-2, indicating potential outliers or activity cliffs. The results show that the HOMO-LUMO energy gap contributed most significantly to the binding affinity. A mean training R (2) of 0.80, a mean test set R (2) of 0.76 and a consensus external test set R (2) of 0.66 were achieved using the QSAR. The training and external test set RMSE values were found to be 0.76 and 0.88. The results suggest that this QSAR model can be used in

  3. [Relationship between two models of personality in old individuals].

    PubMed

    Calvet, Benjamin; Bricaud, Magali; Clément, Jean-Pierre

    2014-12-01

    The relationships between the seven dimensions of the Cloninger psychobiological model and the five factors of the Costa and McCrae model were examined in 54 elderly subjects from the French general population. The dimensions of temperament (novelty seeking, harm avoidance, reward dependence) and character (determination, cooperation, transcendence) from the Cloninger's model were measured by the temperament and character inventory whereas the five factors of Costa and McCrae model (neuroticism, extraversion, openness to experience, agreeableness and conscientiousness) were evaluated using the NEO PI-R. Multiple regression analyses show that some dimensions of the temperament and character inventory predict some dimensions of the Big five and vice versa. Therefore we suggest that the Big five model could be related to brain monoaminergic activities.

  4. Determining cleanup levels in bioremediation: Quantitative structure activity relationship techniques

    SciTech Connect

    Arulgnanendran, V.R.J.; Nirmalakhandan, N.

    1995-12-31

    An important feature in the process of planning and initiating bioremediation is the quantification of the toxicity of either an individual chemical or a group of chemicals when multiple chemicals are involved. A laboratory protocol was developed to test the toxicity of single chemicals and mixtures of organic chemicals in a soil medium. Portions of these chemicals are used as a training set to develop Quantitative Structure Activity Relationship (QSAR) models. These predictive models are tested using the chemicals in the testing set, i.e., the remaining chemicals. Moreover mixtures with 10 contaminants in each mixture are tested experimentally to determine joint toxicity for mixtures of chemicals. Using the concepts of Toxic Units, Additivity Index, and Mixture Toxicity Index, the laboratory results are tested for additive, synergistic, or antagonistic effects of the contaminants. These concepts are further validated on mixtures containing eight chemicals that are tested in the laboratory. In addition to the use of the predictive models in evaluating cleanup levels for hazardous waste locations, they are useful to predict microbial toxicity in soils of new chemicals from a congeneric group acting by the same mode of toxicity. These models are applicable when the contaminants act singly or jointly in a mixture.

  5. Activity composition relationships in silicate melts

    SciTech Connect

    Glazner, A.F.

    1990-01-01

    Equipment progress include furnace construction and electron microprobe installation. The following studies are underway: phase equilibria along basalt-rhyolite mixing line (olivine crystallization from natural silicic andensites, distribution of Fe and Mg between olivine and liquid, dist. of Ca and Na between plagioclase and liquid), enthalpy-composition relations in magmas (bulk heat capacity of alkali basalt), density model for magma ascent and contamination, thermobarometry in igneous systems (olivine/plagioclase phenocryst growth in Quat. basalt), high-pressure phase equilibria of alkali basalt, basalt-quartz mixing experiments, phase equilibria of East African basalts, and granitic minerals in mafic magma. (DLC)

  6. Structure-activity relationships and molecular modelling of new 5-arylidene-4-thiazolidinone derivatives as aldose reductase inhibitors and potential anti-inflammatory agents.

    PubMed

    Maccari, Rosanna; Vitale, Rosa Maria; Ottanà, Rosaria; Rocchiccioli, Marco; Marrazzo, Agostino; Cardile, Venera; Graziano, Adriana Carol Eleonora; Amodeo, Pietro; Mura, Umberto; Del Corso, Antonella

    2014-06-23

    A series of 5-(carbamoylmethoxy)benzylidene-2-oxo/thioxo-4-thiazolidinone derivatives (6-9) were synthesized as inhibitors of aldose reductase (AR), enzyme which plays a crucial role in the development of diabetes complications as well as in the inflammatory processes associated both to diabetes mellitus and to other pathologies. In vitro inhibitory activity indicated that compounds 6-9a-d were generally good AR inhibitors. Acetic acid derivatives 8a-d and 9a-d were shown to be the best enzyme inhibitors among the tested compounds endowed with significant inhibitory ability levels reaching submicromolar IC50 values. Moreover, some representative AR inhibitors (7a, 7c, 9a, 9c, 9d) were assayed in cultures of human keratinocytes in order to evaluate their capability to reduce NF-kB activation and iNOS expression. Compound 9c proved to be the best derivative endowed with both interesting AR inhibitory effectiveness and ability to reduce NF-kB activation and iNOS expression. Molecular docking and molecular dynamics simulations were undertaken to investigate the binding modes of selected compounds into the active site of AR in order to rationalize the inhibitory effectiveness of these derivatives.

  7. Modeling joint effects of mixtures of chemicals on microorganisms using quantitative structure activity relationships. Annual report, 20 August 1991-19 August 1992

    SciTech Connect

    Nirmalakhandan, N.; Mohsin, M.; Arulgnanendran, V.; Bangxin, S.; Cadena, F.

    1992-01-01

    Toxicity of 50 organic chemicals to microorganisms was determined using the respirometeric approach. Using this experimental database, models for predicting toxicity (IC50 values) were developed using QSAR techniques. Toxicity measurements were also made for ten binary mixtures, and sixteen multi-component mixtures. The joint effects of organic chemicals in mixtures were analyzed by three different approaches. Using the QSAR model developed from single chemical studies, an approach was developed to analyze and predict joint effects of chemicals in mixtures. The results of this study indicate that the joint effects could be considered simply additive for the different classes of chemicals tested.

  8. Structure-Activity Relationship of Azaindole-Based Glucokinase Activators.

    PubMed

    Paczal, Attila; Bálint, Balázs; Wéber, Csaba; Szabó, Zoltán B; Ondi, Levente; Theret, Isabelle; De Ceuninck, Frédéric; Bernard, Catherine; Ktorza, Alain; Perron-Sierra, Francoise; Kotschy, András

    2016-01-28

    7-Azaindole has been identified as a novel bidentate anchor point for allosteric glucokinase activators. A systematic investigation around three principal parts of the new small molecule glucokinase activators led to a robust SAR in agreement with structural data that also helped to assess the conformational flexibility of the allosteric activation site. The increase in glucose uptake resulting from glucokinase activation in hepatocytes in vitro translated into the efficient lowering of glucose levels in vivo with the best compounds. PMID:26685731

  9. Pharmacophore modeling of nilotinib as an inhibitor of ATP-binding cassette drug transporters and BCR-ABL kinase using a three-dimensional quantitative structure-activity relationship approach.

    PubMed

    Shukla, Suneet; Kouanda, Abdul; Silverton, Latoya; Talele, Tanaji T; Ambudkar, Suresh V

    2014-07-01

    Nilotinib (Tasigna) is a tyrosine kinase inhibitor approved by the FDA to treat chronic phase chronic myeloid leukemia patients. It is also a transport substrate of the ATP-binding cassette (ABC) drug efflux transporters ABCB1 (P-glycoprotein, P-gp) and ABCG2 (BCRP), which may have an effect on the pharmacokinetics and toxicity of this drug. The goal of this study was to identify pharmacophoric features of nilotinib in order to potentially develop specific inhibitors of BCR-ABL kinase with minimal interactions with ABC drug transporters. Three-dimensional pharmacophore modeling and quantitative structure-activity relationship (QSAR) studies were carried out on a series of nilotinib analogues to identify chemical features that contribute to inhibitory activity of nilotinib against BCR-ABL kinase activity, P-gp, and ABCG2. Twenty-five derivatives of nilotinib were synthesized and were then tested to measure their activity to inhibit BCR-ABL kinase and to inhibit the function of ABC drug transporters. A set of in vitro experiments including kinase activity and cell-based transport assays and photolabeling of P-gp and ABCG2 with a transport substrate, [(125)I]-iodoarylazido-prazosin (IAAP), were carried out in isolated membranes to evaluate the potency of the derivatives to inhibit the function of ABC drug transporters and BCR-ABL kinase. Sixteen, fourteen, and ten compounds were selected as QSAR data sets, respectively, to generate PHASE v3.1 pharmacophore models for BCR-ABL kinase, ABCG2, and P-gp inhibitors. The IC50 values of these derivatives against P-gp, ABCG2, or BCR-ABL kinase were used to generate pharmacophore features required for optimal interactions with these targets. A seven-point pharmacophore (AADDRRR) for BCR-ABL kinase inhibitory activity, a six-point pharmacophore (ADHRRR) for ABCG2 inhibitory activity, and a seven-point pharmacophore (AADDRRR) for P-gp inhibitory activity were generated. The derived models clearly demonstrate high predictive power

  10. Modeling Electrically Active Viscoelastic Membranes

    PubMed Central

    Roy, Sitikantha; Brownell, William E.; Spector, Alexander A.

    2012-01-01

    The membrane protein prestin is native to the cochlear outer hair cell that is crucial to the ear's amplification and frequency selectivity throughout the whole acoustic frequency range. The outer hair cell exhibits interrelated dimensional changes, force generation, and electric charge transfer. Cells transfected with prestin acquire unique active properties similar to those in the native cell that have also been useful in understanding the process. Here we propose a model describing the major electromechanical features of such active membranes. The model derived from thermodynamic principles is in the form of integral relationships between the history of voltage and membrane resultants as independent variables and the charge density and strains as dependent variables. The proposed model is applied to the analysis of an active force produced by the outer hair cell in response to a harmonic electric field. Our analysis reveals the mechanism of the outer hair cell active (isometric) force having an almost constant amplitude and phase up to 80 kHz. We found that the frequency-invariance of the force is a result of interplay between the electrical filtering associated with prestin and power law viscoelasticity of the surrounding membrane. Paradoxically, the membrane viscoelasticity boosts the force balancing the electrical filtering effect. We also consider various modes of electromechanical coupling in membrane with prestin associated with mechanical perturbations in the cell. We consider pressure or strains applied step-wise or at a constant rate and compute the time course of the resulting electric charge. The results obtained here are important for the analysis of electromechanical properties of membranes, cells, and biological materials as well as for a better understanding of the mechanism of hearing and the role of the protein prestin in this mechanism. PMID:22701528

  11. Relationship between participation in leisure activities and constraints on Taiwanese breastfeeding mothers during leisure activities

    PubMed Central

    2013-01-01

    Background Participation in leisure activities strongly associates with health and well-being. Little research has explored the relationship between participation in leisure activities and constraints on breastfeeding mothers during leisure activities. The purposes of this study are: 1) to investigate constraints on breastfeeding mothers during leisure activities and participation in leisure activities; 2) to investigate the differences between preferences for leisure activities and actual participation by breastfeeding mothers; 3) to segment breastfeeding mothers with similar patterns, using a cluster analysis based on the delineated participation in leisure activities and leisure preferences; 4) to explore any differences between clusters of breastfeeding mothers with respect to socio-demographic characteristics, breastfeeding behaviours and leisure constraints. Methods This study has a cross-sectional design using an online survey conducted among mothers having breastfeeding experiences of more than four months. The questionnaire includes demographic variables, breastfeeding behaviours, preferences for leisure activities participation, and constraints on leisure activities. Collection of data occurred between March and July 2011, producing 415 valid responses for analysis. Results For breastfeeding mothers, this study identifies constraints on breastfeeding related to leisure activities in addition to the three traditional factors for constraints in the model. This study demonstrates that reports of constraints related to children, family, and nursing environments are the most frequent. Breastfeeding mothers in Taiwan participate regularly in family activities or activities related to their children. Cluster analysis classified breastfeeding mothers into Action and Contemplation groups, and found that mothers within the latter group participate less in leisure activities and experienced more constraints related to breastfeeding. Conclusions Implications provide

  12. Quantitative structure-antifungal activity relationships of some benzohydrazides against Botrytis cinerea.

    PubMed

    Reino, José L; Saiz-Urra, Liane; Hernandez-Galan, Rosario; Aran, Vicente J; Hitchcock, Peter B; Hanson, James R; Gonzalez, Maykel Perez; Collado, Isidro G

    2007-06-27

    Fourteen benzohydrazides have been synthesized and evaluated for their in vitro antifungal activity against the phytopathogenic fungus Botrytis cinerea. The best antifungal activity was observed for the N',N'-dibenzylbenzohydrazides 3b-d and for the N-aminoisoindoline-derived benzohydrazide 5. A quantitative structure-activity relationship (QSAR) study has been developed using a topological substructural molecular design (TOPS-MODE) approach to interpret the antifungal activity of these synthetic compounds. The model described 98.3% of the experimental variance, with a standard deviation of 4.02. The influence of an ortho substituent on the conformation of the benzohydrazides was investigated by X-ray crystallography and supported by QSAR study. Several aspects of the structure-activity relationships are discussed in terms of the contribution of different bonds to the antifungal activity, thereby making the relationships between structure and biological activity more transparent.

  13. Oriented active shape models.

    PubMed

    Liu, Jiamin; Udupa, Jayaram K

    2009-04-01

    Active shape models (ASM) are widely employed for recognizing anatomic structures and for delineating them in medical images. In this paper, a novel strategy called oriented active shape models (OASM) is presented in an attempt to overcome the following five limitations of ASM: 1) lower delineation accuracy, 2) the requirement of a large number of landmarks, 3) sensitivity to search range, 4) sensitivity to initialization, and 5) inability to fully exploit the specific information present in the given image to be segmented. OASM effectively combines the rich statistical shape information embodied in ASM with the boundary orientedness property and the globally optimal delineation capability of the live wire methodology of boundary segmentation. The latter characteristics allow live wire to effectively separate an object boundary from other nonobject boundaries with similar properties especially when they come very close in the image domain. The approach leads to a two-level dynamic programming method, wherein the first level corresponds to boundary recognition and the second level corresponds to boundary delineation, and to an effective automatic initialization method. The method outputs a globally optimal boundary that agrees with the shape model if the recognition step is successful in bringing the model close to the boundary in the image. Extensive evaluation experiments have been conducted by utilizing 40 image (magnetic resonance and computed tomography) data sets in each of five different application areas for segmenting breast, liver, bones of the foot, and cervical vertebrae of the spine. Comparisons are made between OASM and ASM based on precision, accuracy, and efficiency of segmentation. Accuracy is assessed using both region-based false positive and false negative measures and boundary-based distance measures. The results indicate the following: 1) The accuracy of segmentation via OASM is considerably better than that of ASM; 2) The number of landmarks

  14. Quantitative structure-activity relationship of antifungal activity of rosin derivatives.

    PubMed

    Wang, Hui; Nguyen, Thi Thanh Hien; Li, Shujun; Liang, Tao; Zhang, Yuanyuan; Li, Jian

    2015-01-15

    To develop new rosin-based wood preservatives with good antifungal activity, 24 rosin derivatives were synthesized, bioassay tested with Trametes versicolor and Gloeophyllum trabeum, and subjected to analysis of their quantitative structure-activity relationships (QSAR). A QSAR analysis using Ampac 9.2.1 and Codessa 2.7.16 software built two QSAR models of antifungal ratio for T. versicolor and G. trabeum with values of R(2)=0.9740 and 0.9692, respectively. Based on the models, tri-N-(3-hydroabietoxy-2-hydroxy) propyl-triethyl ammonium chloride was designed and the bioassay test result proved its better inhibitory effect against the two selected fungi as expected.

  15. Quantitative structure-activity relationship of antifungal activity of rosin derivatives.

    PubMed

    Wang, Hui; Nguyen, Thi Thanh Hien; Li, Shujun; Liang, Tao; Zhang, Yuanyuan; Li, Jian

    2015-01-15

    To develop new rosin-based wood preservatives with good antifungal activity, 24 rosin derivatives were synthesized, bioassay tested with Trametes versicolor and Gloeophyllum trabeum, and subjected to analysis of their quantitative structure-activity relationships (QSAR). A QSAR analysis using Ampac 9.2.1 and Codessa 2.7.16 software built two QSAR models of antifungal ratio for T. versicolor and G. trabeum with values of R(2)=0.9740 and 0.9692, respectively. Based on the models, tri-N-(3-hydroabietoxy-2-hydroxy) propyl-triethyl ammonium chloride was designed and the bioassay test result proved its better inhibitory effect against the two selected fungi as expected. PMID:25466709

  16. Structure - membrane activity relationship in a family of peptide-based gemini amphiphiles: An insight from experimental and theoretical model systems.

    PubMed

    Korchowiec, Beata; Gorczyca, Marcelina; Korchowiec, Jacek; Rubio-Magnieto, Jenifer; Lotfallah, Ahmed H; Luis, Santiago V; Rogalska, Ewa

    2016-10-01

    A study of the interaction between five gemini amphiphilic valine-based pseudopeptides (GAPs) differing by the length of the central aliphatic spacer linking two amino acid subunits, and a model bacterial membrane lipid, 1,2-dimyristoyl-sn-glycero-3-phospho-rac-(1-glycerol) (DMPG), is here presented. Pure DMPG, pure GAPs and mixed GAPs/DMPG monolayers were formed at the air-water interface using Langmuir technique. The properties of the Langmuir films were investigated using surface pressure measurements, polarization modulation-infrared reflection-absorption spectroscopy, and Brewster angle microscopy. The atomic level information concerning the orientation of molecules in the monolayer and hydration of the polar headgroups was obtained from molecular dynamics simulations. It was demonstrated that the length of the central spacer in the GAPs structure is important for the properties of the mixed films; the disorganization of the membrane increases with the length of the spacer. The latter point is important for developing possible antimicrobial agents based on GAPs.

  17. Adapting interrelated two-way clustering method for quantitative structure-activity relationship (QSAR) modeling of mutagenicity/non- mutagenicity of a diverse set of chemicals.

    PubMed

    Majumdar, Subhabrata; Basak, Subhash C; Grunwald, Gregory D

    2013-12-01

    Interrelated Two-way Clustering (ITC) is an unsupervised clustering method developed to divide samples into two groups in gene expression data obtained through microarrays, selecting important genes simultaneously in the process. This has been found to be a better approach than conventional clustering methods like K-means or selforganizing map for the scenarios when number of samples is much smaller than number of variables (n«p). In this paper we used the ITC approach for classification of a diverse set of 508 chemicals regarding mutagenicity. A large number of topological indices (TIs), 3-dimensional, and quantum chemical descriptors, as well as atom pairs (APs) has been used as explanatory variables. In this paper, ITC has been used only for predictor selection, after which ridge regression is employed to build the final predictive model. The proper leave-one-out (LOO) method of cross-validation in this scenario is to take as holdout each of the 508 compounds before predictor thinning and compare the predicted values with the experimental data. ITC based results obtained here are comparable to those developed earlier.

  18. Organizational Models of Medical School Relationships to the Clinical Enterprise.

    ERIC Educational Resources Information Center

    Culbertson, Richard A.; And Others

    1996-01-01

    Analyzed existing relationships between medical schools and clinical enterprises to develop models of these relationships. Four conceptual models were identified: (1) "single ownership, owned integrated system"; (2) "general partner"; (3) "limited partner"; and (4) "wholly owned, subsidiary." The advantages and disadvantages of each model are…

  19. 4,6-Diphenylpyridines as Promising Novel Anti-Influenza Agents Targeting the PA-PB1 Protein-Protein Interaction: Structure-Activity Relationships Exploration with the Aid of Molecular Modeling.

    PubMed

    Trist, Iuni M L; Nannetti, Giulio; Tintori, Cristina; Fallacara, Anna Lucia; Deodato, Davide; Mercorelli, Beatrice; Palù, Giorgio; Wijtmans, Maikel; Gospodova, Tzveta; Edink, Ewald; Verheij, Mark; de Esch, Iwan; Viteva, Lilia; Loregian, Arianna; Botta, Maurizio

    2016-03-24

    Influenza is an infectious disease that represents an important public health burden, with high impact on the global morbidity, mortality, and economy. The poor protection and the need of annual updating of the anti-influenza vaccine, added to the rapid emergence of viral strains resistant to current therapy make the need for antiviral drugs with novel mechanisms of action compelling. In this regard, the viral RNA polymerase is an attractive target that allows the design of selective compounds with reduced risk of resistance. In previous studies we showed that the inhibition of the polymerase acidic protein-basic protein 1 (PA-PB1) interaction is a promising strategy for the development of anti-influenza agents. Starting from the previously identified 3-cyano-4,6-diphenyl-pyridines, we chemically modified this scaffold and explored its structure-activity relationships. Noncytotoxic compounds with both the ability of disrupting the PA-PB1 interaction and antiviral activity were identified, and their mechanism of target binding was clarified with molecular modeling simulations. PMID:26924568

  20. Synthesis, Structure-Activity Relationships (SAR) and in Silico Studies of Coumarin Derivatives with Antifungal Activity

    PubMed Central

    de Araújo, Rodrigo S. A.; Guerra, Felipe Q. S.; de O. Lima, Edeltrudes; de Simone, Carlos A.; Tavares, Josean F.; Scotti, Luciana; Scotti, Marcus T.; de Aquino, Thiago M.; de Moura, Ricardo O.; Mendonça, Francisco J. B.; Barbosa-Filho, José M.

    2013-01-01

    The increased incidence of opportunistic fungal infections, associated with greater resistance to the antifungal drugs currently in use has highlighted the need for new solutions. In this study twenty four coumarin derivatives were screened in vitro for antifungal activity against strains of Aspergillus. Some of the compounds exhibited significant antifungal activity with MICs values ranging between 16 and 32 μg/mL. The structure-activity relationships (SAR) study demonstrated that O-substitutions are essential for antifungal activity. It also showed that the presence of a short aliphatic chain and/or electron withdrawing groups (NO2 and/or acetate) favor activity. These findings were confirmed using density functional theory (DFT), when calculating the LUMO density. In Principal Component Analysis (PCA), two significant principal components (PCs) explained more than 60% of the total variance. The best Partial Least Squares Regression (PLS) model showed an r2 of 0.86 and q2cv of 0.64 corroborating the SAR observations as well as demonstrating a greater probe N1 interaction for active compounds. Descriptors generated by TIP correlogram demonstrated the importance of the molecular shape for antifungal activity. PMID:23306152

  1. Molecular determinants of ligand binding modes in the histamine H(4) receptor: linking ligand-based three-dimensional quantitative structure-activity relationship (3D-QSAR) models to in silico guided receptor mutagenesis studies.

    PubMed

    Istyastono, Enade P; Nijmeijer, Saskia; Lim, Herman D; van de Stolpe, Andrea; Roumen, Luc; Kooistra, Albert J; Vischer, Henry F; de Esch, Iwan J P; Leurs, Rob; de Graaf, Chris

    2011-12-01

    The histamine H(4) receptor (H(4)R) is a G protein-coupled receptor (GPCR) that plays an important role in inflammation. Similar to the homologous histamine H(3) receptor (H(3)R), two acidic residues in the H(4)R binding pocket, D(3.32) and E(5.46), act as essential hydrogen bond acceptors of positively ionizable hydrogen bond donors in H(4)R ligands. Given the symmetric distribution of these complementary pharmacophore features in H(4)R and its ligands, different alternative ligand binding mode hypotheses have been proposed. The current study focuses on the elucidation of the molecular determinants of H(4)R-ligand binding modes by combining (3D) quantitative structure-activity relationship (QSAR), protein homology modeling, molecular dynamics simulations, and site-directed mutagenesis studies. We have designed and synthesized a series of clobenpropit (N-(4-chlorobenzyl)-S-[3-(4(5)-imidazolyl)propyl]isothiourea) derivatives to investigate H(4)R-ligand interactions and ligand binding orientations. Interestingly, our studies indicate that clobenpropit (2) itself can bind to H(4)R in two distinct binding modes, while the addition of a cyclohexyl group to the clobenpropit isothiourea moiety allows VUF5228 (5) to adopt only one specific binding mode in the H(4)R binding pocket. Our ligand-steered, experimentally supported protein modeling method gives new insights into ligand recognition by H(4)R and can be used as a general approach to elucidate the structure of protein-ligand complexes.

  2. The relationship between trunk muscle activation and trunk stiffness: examining a non-constant stiffness gain.

    PubMed

    Brown, Stephen H M; McGill, Stuart M

    2010-12-01

    The relationship between muscle activation, force and stiffness needs to be known to interpret the stability state of the spine. To test the relationship between these variables, a quick release approach was used to match quantified torso stiffness with an EMG activation-based estimate of individual muscle stiffnesses. The relationship between activation, force and stiffness was modelled as k = q x F/l, where k, F and l are muscle stiffness, force and length, respectively, and q is the dimensionless stiffness gain relating these variables. Under the tested experimental scenario, the 'stiffness gain', q, which linked activation with stiffness, demonstrated a decreasing trend with increasing levels of torso muscle activation. This highlights the likelihood that the choice of a single q value may be over simplistic to relate force to stiffness in muscles that control the spine. This has implications for understanding the potential for spine instability in situations requiring high muscular demand.

  3. Data Base Design Using Entity-Relationship Models.

    ERIC Educational Resources Information Center

    Davis, Kathi Hogshead

    1983-01-01

    The entity-relationship (ER) approach to database design is defined, and a specific example of an ER model (personnel-payroll) is examined. The requirements for converting ER models into specific database management systems are discussed. (Author/MSE)

  4. Dynamic causal modelling of brain-behaviour relationships.

    PubMed

    Rigoux, L; Daunizeau, J

    2015-08-15

    In this work, we expose a mathematical treatment of brain-behaviour relationships, which we coin behavioural Dynamic Causal Modelling or bDCM. This approach aims at decomposing the brain's transformation of stimuli into behavioural outcomes, in terms of the relative contribution of brain regions and their connections. In brief, bDCM places the brain at the interplay between stimulus and behaviour: behavioural outcomes arise from coordinated activity in (hidden) neural networks, whose dynamics are driven by experimental inputs. Estimating neural parameters that control network connectivity and plasticity effectively performs a neurobiologically-constrained approximation to the brain's input-outcome transform. In other words, neuroimaging data essentially serves to enforce the realism of bDCM's decomposition of input-output relationships. In addition, post-hoc artificial lesions analyses allow us to predict induced behavioural deficits and quantify the importance of network features for funnelling input-output relationships. This is important, because this enables one to bridge the gap with neuropsychological studies of brain-damaged patients. We demonstrate the face validity of the approach using Monte-Carlo simulations, and its predictive validity using empirical fMRI/behavioural data from an inhibitory control task. Lastly, we discuss promising applications of this work, including the assessment of functional degeneracy (in the healthy brain) and the prediction of functional recovery after lesions (in neurological patients).

  5. Testing causal models of the relationship between childhood gender atypical behaviour and parent-child relationship.

    PubMed

    Alanko, Katarina; Santtila, Pekka; Salo, Benny; Jern, Patrik; Johansson, Ada; Sandnabba, N Kenneth

    2011-06-01

    An association between childhood gender atypical behaviour (GAB) and a negative parent-child relationship has been demonstrated in several studies, yet the causal relationship of this association is not fully understood. In the present study, different models of causation between childhood GAB and parent-child relationships were tested. Direction of causation modelling was applied to twin data from a population-based sample (n= 2,565) of Finnish 33- to 43-year-old twins. Participants completed retrospective self-report questionnaires. Five different models of causation were then fitted to the data: GAB → parent-child relationship, parent-child relationship → GAB, reciprocal causation, a bivariate genetic model, and a model assuming no correlation. It was found that a model in which GAB and quality of mother-child, and father-child relationship reciprocally affect each other best fitted the data. The findings are discussed in light of how we should understand, including causality, the association between GAB and parent-child relationship.

  6. Development of structure-activity relationship for metal oxide nanoparticles

    NASA Astrophysics Data System (ADS)

    Liu, Rong; Zhang, Hai Yuan; Ji, Zhao Xia; Rallo, Robert; Xia, Tian; Chang, Chong Hyun; Nel, Andre; Cohen, Yoram

    2013-05-01

    Nanomaterial structure-activity relationships (nano-SARs) for metal oxide nanoparticles (NPs) toxicity were investigated using metrics based on dose-response analysis and consensus self-organizing map clustering. The NP cellular toxicity dataset included toxicity profiles consisting of seven different assays for human bronchial epithelial (BEAS-2B) and murine myeloid (RAW 264.7) cells, over a concentration range of 0.39-100 mg L-1 and exposure time up to 24 h, for twenty-four different metal oxide NPs. Various nano-SAR building models were evaluated, based on an initial pool of thirty NP descriptors. The conduction band energy and ionic index (often correlated with the hydration enthalpy) were identified as suitable NP descriptors that are consistent with suggested toxicity mechanisms for metal oxide NPs and metal ions. The best performing nano-SAR with the above two descriptors, built with support vector machine (SVM) model and of validated robustness, had a balanced classification accuracy of ~94%. An applicability domain for the present data was established with a reasonable confidence level of 80%. Given the potential role of nano-SARs in decision making, regarding the environmental impact of NPs, the class probabilities provided by the SVM nano-SAR enabled the construction of decision boundaries with respect to toxicity classification under different acceptance levels of false negative relative to false positive predictions.Nanomaterial structure-activity relationships (nano-SARs) for metal oxide nanoparticles (NPs) toxicity were investigated using metrics based on dose-response analysis and consensus self-organizing map clustering. The NP cellular toxicity dataset included toxicity profiles consisting of seven different assays for human bronchial epithelial (BEAS-2B) and murine myeloid (RAW 264.7) cells, over a concentration range of 0.39-100 mg L-1 and exposure time up to 24 h, for twenty-four different metal oxide NPs. Various nano-SAR building models were

  7. Examining the Relationship between Physical Models and Students' Science Practices

    NASA Astrophysics Data System (ADS)

    Miller, Alison Riley

    Scientists engage with practices like model development and use, data analysis and interpretation, explanation construction, and argumentation in order to expand the frontiers of science, so it can be inferred that students' engagement with science practices may help them deepen their own science understanding. As one of three dimensions on which the Next Generation Science Standards is built, science practices are recognized as an important component of science instruction. However, the contexts in which these practices happen are under-researched. Furthermore, research on science practices among students tends to focus on one or two practices in isolation when, in reality, students and scientists tend to engage with multiple overlapping practices. This study focused on identifying and characterizing multiple science practices as eighth and ninth-grade Earth Science students participated in a small group collaborative problem solving activity both with and without the use of a physical model. This study found a range of sophistication in the observed science practices as well as a relationship between the frequency of those practices and the accuracy of the groups' outcomes. Based on this relationship, groups were assigned to one of three categories. Further analysis revealed that model use varied among the three categories of groups. Comparisons across these three group categories suggest that there may be a bootstrapping relationship between students' engagement with science practices and the development of their content understanding. This metaphor of bootstrapping is used to represent how students may develop deeper science content understanding through engagement with science practices and concurrently develop greater facility with science practices as they learn science content. Implications are presented for curriculum designers, teachers and teacher educators. These include recommendations for curriculum design that encourage structured opportunities for

  8. Predicting anti-androgenic activity of bisphenols using molecular docking and quantitative structure-activity relationships.

    PubMed

    Yang, Xianhai; Liu, Huihui; Yang, Qian; Liu, Jining; Chen, Jingwen; Shi, Lili

    2016-11-01

    Both in vivo and in vitro assay indicated that bisphenols can inhibit the androgen receptor. However, the underlying antagonistic mechanism is unclear. In this study, molecular docking was employed to probe the interaction mechanism between bisphenols and human androgen receptor (hAR). The binding pattern of ligands in hAR crystal structures was also analyzed. Results show that hydrogen bonding and hydrophobic interactions are the dominant interactions between the ligands and hAR. The critical amino acid residues involved in forming hydrogen bonding between bisphenols and hAR is Asn 705 and Gln 711. Furthermore, appropriate molecular structural descriptors were selected to characterize the non-bonded interactions. Stepwise multiple linear regressions (MLR) analysis was employed to develop quantitative structure-activity relationship (QSAR) models for predicting the anti-androgenic activity of bisphenols. Based on the QSAR development and validation guideline issued by OECD, the goodness-of-fit, robustness and predictive ability of constructed QSAR model were assessed. The model application domain was characterized by the Euclidean distance and Williams plot. The mechanisms of the constructed model were also interpreted based on the selected molecular descriptors i.e. the number of hydroxyl groups (nROH), the most positive values of the molecular surface potential (Vs,max) and the lowest unoccupied molecular orbital energy (ELUMO). Finally, based on the model developed, the data gap for other twenty-six bisphenols on their anti-androgenic activity was filled. The predicted results indicated that the anti-androgenic activity of seven bisphenols was higher than that of bisphenol A. PMID:27561732

  9. Using theoretical descriptors in structure activity relationships: Validating toxicity predictions

    SciTech Connect

    Famini, G.R.; Wilson, L.Y.; Chester, N.A.; Sterling, P.A.

    1995-12-01

    Quantitative Structure Activity Relationships (QSAR) and Linear Free Energy Relationships (LFER) are very useful for correlating toxicological data, and in characterizating trends in terms of structural and electronic effects. Several years ago, we developed a series of equations correlating a number of toxicity tests with theoretically determined descriptors. One of these tests was the Microtox test, using the degradation in light from Photobacteriurn phosphoreum. Recently, several new compounds have been tested in our laboratory using the Microtox test, and compared against the predicted values. The agreement between experimental and theoretical results will be discussed, as will reasons for {open_quotes}good{close_quotes} or {open_quotes}poor{close_quotes} predictions.

  10. Relationships among certain joint constitutive models.

    SciTech Connect

    Segalman, Daniel Joseph; Starr, Michael James

    2004-09-01

    In a recent paper, Starr and Segalman demonstrated that any Masing model can be represented as a parallel-series Iwan model. A preponderance of the constitutive models that have been suggested for simulating mechanical joints are Masing models, and the purpose of this discussion is to demonstrate how the Iwan representation of those models can yield insight into their character. In particular, this approach can facilitate a critical comparison among numerous plausible constitutive models. It is explicitly shown that three-parameter models such as Smallwood's (Ramberg-Osgood) calculate parameters in such a manner that macro-slip is not an independent parameter, yet the model admits macro-slip. The introduction of a fourth parameter is therefore required. It is shown that when a macro-slip force is specified for the Smallwood model the result is a special case of the Segalman four-parameter model. Both of these models admit a slope discontinuity at the inception of macro-slip. A five-parameter model that has the beneficial features of Segalman's four-parameter model is proposed. This model manifests a force-displacement curve having a continuous first derivative.

  11. The First Structure–Activity Relationship Studies for Designer Receptors Exclusively Activated by Designer Drugs

    PubMed Central

    2016-01-01

    Over the past decade, two independent technologies have emerged and been widely adopted by the neuroscience community for remotely controlling neuronal activity: optogenetics which utilize engineered channelrhodopsin and other opsins, and chemogenetics which utilize engineered G protein-coupled receptors (Designer Receptors Exclusively Activated by Designer Drugs (DREADDs)) and other orthologous ligand–receptor pairs. Using directed molecular evolution, two types of DREADDs derived from human muscarinic acetylcholine receptors have been developed: hM3Dq which activates neuronal firing, and hM4Di which inhibits neuronal firing. Importantly, these DREADDs were not activated by the native ligand acetylcholine (ACh), but selectively activated by clozapine N-oxide (CNO), a pharmacologically inert ligand. CNO has been used extensively in rodent models to activate DREADDs, and although CNO is not subject to significant metabolic transformation in mice, a small fraction of CNO is apparently metabolized to clozapine in humans and guinea pigs, lessening the translational potential of DREADDs. To effectively translate the DREADD technology, the next generation of DREADD agonists are needed and a thorough understanding of structure–activity relationships (SARs) of DREADDs is required for developing such ligands. We therefore conducted the first SAR studies of hM3Dq. We explored multiple regions of the scaffold represented by CNO, identified interesting SAR trends, and discovered several compounds that are very potent hM3Dq agonists but do not activate the native human M3 receptor (hM3). We also discovered that the approved drug perlapine is a novel hM3Dq agonist with >10 000-fold selectivity for hM3Dq over hM3. PMID:25587888

  12. Exploring the Relationship between Situated Activity and CALL Learning in Teacher Education

    ERIC Educational Resources Information Center

    McNeil, Levi

    2013-01-01

    Situated learning is often proposed as a model for CALL teacher education. However, we know little about how students perceive situated CALL coursework and activities, and the nature of the relationship between situated learning and CALL learning. This exploratory case study addresses these issues. Survey, questionnaire, and open-ended data were…

  13. (Quantitative structure-activity relationships in environmental toxicology)

    SciTech Connect

    Turner, J.E.

    1990-10-04

    The traveler attended the Fourth International Workshop on QSAR (Quantitative Structure-Activity Relationships) in Environmental Toxicology. He was an author or co-author on one platform and two poster presentations. The subject of the workshop offers a framework for analyzing and predicting the fate of chemical pollutants in organisms and the environment. QSAR is highly relevant to the ORNL program on the physicochemical characterization of chemical pollutants for health protection.

  14. Modeling the Relationship between Prosodic Sensitivity and Early Literacy

    ERIC Educational Resources Information Center

    Holliman, Andrew; Critten, Sarah; Lawrence, Tony; Harrison, Emily; Wood, Clare; Hughes, David

    2014-01-01

    A growing literature has demonstrated that prosodic sensitivity is related to early literacy development; however, the precise nature of this relationship remains unclear. It has been speculated in recent theoretical models that the observed relationship between prosodic sensitivity and early literacy might be partially mediated by children's…

  15. Love Relationships: Attachment Style and the Investment Model.

    ERIC Educational Resources Information Center

    Pistole, Carole M.; And Others

    1995-01-01

    Examined association of adult attachment styles and Rusbult's investment model of relationships. Responses from 239 participants indicated those who are securely attached experience greater satisfaction, fewer costs, and greater commitment in their relationships than do other attachment groups. Other findings and implications for counseling were…

  16. What do sexually active adolescent females say about relationship issues?

    PubMed

    Bralock, Anita; Koniak-Griffin, Deborah

    2009-04-01

    Many sexually active teenagers face risk for contracting sexually transmitted infections (STIs) including HIV. The purpose of our study was to gain an understanding about influences on condom use among sexually active adolescents in relationships. Data were collected through semi-structured openended interviews. The findings of this study suggest that many adolescents desired the love of a male partner, and were willing to concede to his request of practicing unprotected sex. Findings support the urgent need for interventions that will promote skill-building techniques to negotiate safer sex behaviors among youth who are most likely to be exposed to STIs through risky behaviors.

  17. What do sexually active adolescent females say about relationship issues?

    PubMed

    Bralock, Anita; Koniak-Griffin, Deborah

    2009-04-01

    Many sexually active teenagers face risk for contracting sexually transmitted infections (STIs) including HIV. The purpose of our study was to gain an understanding about influences on condom use among sexually active adolescents in relationships. Data were collected through semi-structured openended interviews. The findings of this study suggest that many adolescents desired the love of a male partner, and were willing to concede to his request of practicing unprotected sex. Findings support the urgent need for interventions that will promote skill-building techniques to negotiate safer sex behaviors among youth who are most likely to be exposed to STIs through risky behaviors. PMID:19268234

  18. Quantitative structure-activity relationships of antimicrobial fatty acids and derivatives against Staphylococcus aureus *

    PubMed Central

    Zhang, Hui; Zhang, Lu; Peng, Li-juan; Dong, Xiao-wu; Wu, Di; Wu, Vivian Chi-Hua; Feng, Feng-qin

    2012-01-01

    Fatty acids and derivatives (FADs) are resources for natural antimicrobials. In order to screen for additional potent antimicrobial agents, the antimicrobial activities of FADs against Staphylococcus aureus were examined using a microplate assay. Monoglycerides of fatty acids were the most potent class of fatty acids, among which monotridecanoin possessed the most potent antimicrobial activity. The conventional quantitative structure-activity relationship (QSAR) and comparative molecular field analysis (CoMFA) were performed to establish two statistically reliable models (conventional QSAR: R 2=0.942, Q 2 LOO=0.910; CoMFA: R 2=0.979, Q 2=0.588, respectively). Improved forecasting can be achieved by the combination of these two models that provide a good insight into the structure-activity relationships of the FADs and that may be useful to design new FADs as antimicrobial agents. PMID:22302421

  19. Phenotypic models of T cell activation.

    PubMed

    Lever, Melissa; Maini, Philip K; van der Merwe, P Anton; Dushek, Omer

    2014-09-01

    T cell activation is a crucial checkpoint in adaptive immunity, and this activation depends on the binding parameters that govern the interactions between T cell receptors (TCRs) and peptide-MHC complexes (pMHC complexes). Despite extensive experimental studies, the relationship between the TCR-pMHC binding parameters and T cell activation remains controversial. To make sense of conflicting experimental data, a variety of verbal and mathematical models have been proposed. However, it is currently unclear which model or models are consistent or inconsistent with experimental data. A key problem is that a direct comparison between the models has not been carried out, in part because they have been formulated in different frameworks. For this Analysis article, we reformulated published models of T cell activation into phenotypic models, which allowed us to directly compare them. We find that a kinetic proofreading model that is modified to include limited signalling is consistent with the majority of published data. This model makes the intriguing prediction that the stimulation hierarchy of two different pMHC complexes (or two different TCRs that are specific for the same pMHC complex) may reverse at different pMHC concentrations.

  20. A review of the global relationship among freshwater fish, autotrophic activity, and regional climate

    USGS Publications Warehouse

    Deines, Andrew M.; Bunnell, David B.; Rogers, Mark W.; Beard, T. Douglas; Taylor, William W.

    2015-01-01

    The relationship between autotrophic activity and freshwater fish populations is an important consideration for ecologists describing trophic structure in aquatic communities, fisheries managers tasked with increasing sustainable fisheries development, and fish farmers seeking to maximize production. Previous studies of the empirical relationships of autotrophic activity and freshwater fish yield have found positive relationships but were limited by small sample sizes, small geographic scopes, and the inability to compare patterns among many types of measurement techniques. Individual studies and reviews have also lacked consistent consideration of regional climate factors which may inform relationships between fisheries and autotrophic activity. We compiled data from over 700 freshwater systems worldwide and used meta-analysis and linear models to develop a comprehensive global synthesis between multiple metrics of autotrophic activity, fisheries, and climate indicators. Our results demonstrate that multiple metrics of fish (i.e., catch per unit effort, yield, and production) increase with autotrophic activity across a variety of fisheries. At the global scale additional variation in this positive relationship can be ascribed to regional climate differences (i.e., temperature and precipitation) across systems. Our results provide a method and proof-of-concept for assessing inland fisheries production at the global scale, where current estimates are highly uncertain, and may therefore inform the continued sustainable use of global inland fishery resources.

  1. The Relationships between Modelling and Argumentation from the Perspective of the Model of Modelling Diagram

    ERIC Educational Resources Information Center

    Mendonça, Paula Cristina Cardoso; Justi, Rosária

    2013-01-01

    Some studies related to the nature of scientific knowledge demonstrate that modelling is an inherently argumentative process. This study aims at discussing the relationship between modelling and argumentation by analysing data collected during the modelling-based teaching of ionic bonding and intermolecular interactions. The teaching activities…

  2. STRUCTURE-ACTIVITY RELATIONSHIP STUIDES AND THEIR ROLE IN PREDICTING AND INVESTIGATING CHEMICAL TOXICITY

    EPA Science Inventory

    Structure-Activity Relationship Studies and their Role in Predicting and Investigating Chemical Toxicity

    Structure-activity relationships (SAR) represent attempts to generalize chemical information relative to biological activity for the twin purposes of generating insigh...

  3. Relationships between sleep, physical activity and human health

    PubMed Central

    Atkinson, Greg; Davenne, Damien

    2009-01-01

    Although sleep and exercise may seem to be mediated by completely different physiological mechanisms, there is growing evidence for clinically important relationships between these two behaviors. It is known that passive body heating facilitates the nocturnal sleep of healthy elderly people with insomnia. This finding supports the hypothesis that changes in body temperature trigger somnogenic brain areas to initiate sleep. Nevertheless, little is known about how the core and distal thermoregulatory responses to exercise fit into this hypothesis. Such knowledge could also help in reducing sleep problems associated with nocturnal shiftwork. It is difficult to incorporate physical activity into a shiftworker's lifestyle, since it is already disrupted in terms of family commitments and eating habits. A multi-research strategy is needed to identify what the optimal amounts and timing of physical activity are for reducing shiftwork-related sleep problems. The relationships between sleep, exercise and diet are also important, given the recently reported associations between short sleep length and obesity. The cardiovascular safety of exercise timing should also be considered, since recent data suggest that the reactivity of blood pressure to a change in general physical activity is highest during the morning. This time is associated with an increased risk in general of a sudden cardiac event, but more research work is needed to separate the influences of light, posture and exercise per se on the haemodynamic responses to sleep and physical activity following sleep taken at night and during the day as a nap. PMID:17067643

  4. Relationships between sleep, physical activity and human health.

    PubMed

    Atkinson, Greg; Davenne, Damien

    2007-02-28

    Although sleep and exercise may seem to be mediated by completely different physiological mechanisms, there is growing evidence for clinically important relationships between these two behaviors. It is known that passive body heating facilitates the nocturnal sleep of healthy elderly people with insomnia. This finding supports the hypothesis that changes in body temperature trigger somnogenic brain areas to initiate sleep. Nevertheless, little is known about how the core and distal thermoregulatory responses to exercise fit into this hypothesis. Such knowledge could also help in reducing sleep problems associated with nocturnal shiftwork. It is difficult to incorporate physical activity into a shiftworker's lifestyle, since it is already disrupted in terms of family commitments and eating habits. A multi-research strategy is needed to identify what the optimal amounts and timing of physical activity are for reducing shiftwork-related sleep problems. The relationships between sleep, exercise and diet are also important, given the recently reported associations between short sleep length and obesity. The cardiovascular safety of exercise timing should also be considered, since recent data suggest that the reactivity of blood pressure to a change in general physical activity is highest during the morning. This time is associated with an increased risk in general of a sudden cardiac event, but more research work is needed to separate the influences of light, posture and exercise per se on the haemodynamic responses to sleep and physical activity following sleep taken at night and during the day as a nap.

  5. Investigating the Relationship between Students' Views of Scientific Models and Their Development of Models

    ERIC Educational Resources Information Center

    Cheng, Meng-Fei; Lin, Jang-Long

    2015-01-01

    Understanding the nature of models and engaging in modeling practice have been emphasized in science education. However, few studies discuss the relationships between students' views of scientific models and their ability to develop those models. Hence, this study explores the relationship between students' views of scientific models and their…

  6. Cookie-Ases: Interactive Models for Teaching Genotype-Phenotype Relationships

    ERIC Educational Resources Information Center

    Seipelt, Rebecca L.

    2006-01-01

    Several hands-on and wet laboratory activities have been proposed to model the genetic concepts of genotypes and phenotypes and their relationship. The exercise presented in this article is a novel, time effective, student-centered, role-playing activity in which students learn about the intricate connection between genotype and phenotype by…

  7. The Relationship among Faculty Appointments and Scholarly Activities

    ERIC Educational Resources Information Center

    Gonzalez, Lynn Passmore

    2010-01-01

    The mission of higher education and the activities of faculty are often described in terms of teaching, research, and service. Additionally, tenure has been the standard model for employment in American college and universities since 1940. The traditional model of faculty earning tenure through high standards of teaching, research, and service is…

  8. The relationship between memory complaints, activity and perceived health status.

    PubMed

    Lee, P-L

    2014-04-01

    Subjective memory complaints (SMC) is a possible symptom of mild cognitive impairment which may progress to dementia. The present study examines the relationship of physical activity (PA), cognitive activity (CA), social activity (SA), and perceived health status (HS) with SMC for middle age and older adults. Participants were from the MIDUS II study (Midlife in the United States) recruited in 2004-2006 (Mean age = 55.99; N = 3030). Hierarchical multiple regression was performed with SMC as the dependent variable, along with PA, CA, SA, and HS as the independent variables. The study revealed that SMC was strongly related to PA, CA, and HS, while controlling covariates. Further, HS had the strongest link with SMC among these predictors while interaction effects (PA × HS, CA × HS, and SA × HS) were insignificant. In addition, different results were achieved in younger versus older groups. Participants with more CA, PA and perception of better health had lower frequency of memory complaints. PMID:24646046

  9. Neuroprotective and Antioxidant Activities of 4-Methylcoumarins: Development of Structure-Activity Relationships.

    PubMed

    Malhotra, Shashwat; Tavakkoli, Marjan; Edraki, Najmeh; Miri, Ramin; Sharma, Sunil Kumar; Prasad, Ashok Kumar; Saso, Luciano; Len, Christophe; Parmar, Virinder Singh; Firuzi, Omidreza

    2016-01-01

    Coumarins are a major class of polyphenols that are abundantly present in many dietary plants and possess different biological activities. Neuroprotective effect of 28 variously substituted 4-methylcoumarins was evaluated in a cell model of oxidative stress-induced neurodegeneration, which measures viability in PC12 cells challenged with hydrogen peroxide by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. The inhibitory activity of these compounds against intracellular reactive oxygen species (ROS) formation was also determined by 2',7'-dichlorofluorescein diacetate method in the same cells. Chemical redox-based assays including 2,2-diphenyl-1-picrylhydrazyl (DPPH) and ferric reducing antioxidant power (FRAP) tests were employed to explore structure-antioxidant activity relationships in a cell-free environment. The results demonstrated that 4-methylcoumarins containing ortho-dihydroxy or ortho-diacetoxy substituents on the benzenoid ring possess considerable neuroprotective effects. ortho-Dihydroxy compounds inhibited cytotoxicity (44.7-62.9%) and ROS formation (41.6-71.1%) at 50 µM and showed considerable antioxidant effects. We conclude that 4-methylcoumarins are promising neuroprotective and antioxidant scaffolds potentially usefull for management of neurodegenerative diseases. PMID:27582333

  10. Modeling approaches for active systems

    NASA Astrophysics Data System (ADS)

    Herold, Sven; Atzrodt, Heiko; Mayer, Dirk; Thomaier, Martin

    2006-03-01

    To solve a wide range of vibration problems with the active structures technology, different simulation approaches for several models are needed. The selection of an appropriate modeling strategy is depending, amongst others, on the frequency range, the modal density and the control target. An active system consists of several components: the mechanical structure, at least one sensor and actuator, signal conditioning electronics and the controller. For each individual part of the active system the simulation approaches can be different. To integrate the several modeling approaches into an active system simulation and to ensure a highly efficient and accurate calculation, all sub models must harmonize. For this purpose, structural models considered in this article are modal state-space formulations for the lower frequency range and transfer function based models for the higher frequency range. The modal state-space formulations are derived from finite element models and/or experimental modal analyses. Consequently, the structure models which are based on transfer functions are directly derived from measurements. The transfer functions are identified with the Steiglitz-McBride iteration method. To convert them from the z-domain to the s-domain a least squares solution is implemented. An analytical approach is used to derive models of active interfaces. These models are transferred into impedance formulations. To couple mechanical and electrical sub-systems with the active materials, the concept of impedance modeling was successfully tested. The impedance models are enhanced by adapting them to adequate measurements. The controller design strongly depends on the frequency range and the number of modes to be controlled. To control systems with a small number of modes, techniques such as active damping or independent modal space control may be used, whereas in the case of systems with a large number of modes or with modes that are not well separated, other control

  11. Quantitative structure-activity relationship (QSAR) study of a series of benzimidazole derivatives as inhibitors of Saccharomyces cerevisiae.

    PubMed

    Podunavac-Kuzmanović, Sonja O; Cvetković, Dragoljub D; Jevrić, Lidija R; Uzelac, Natasa J

    2013-01-01

    A quantitative structure activity relationship (QSAR) has been carried out on a series of benzimidazole derivatives to identify the structural requirements for their inhibitory activity against yeast Saccharomyces cerevisiae. A multiple linear regression (MLR) procedure was used to model the relationships between various physicochemical, steric, electronic, and structural molecular descriptors and antifungal activity of benzimidazole derivatives. The QSAR expressions were generated using a training set of 16 compounds and the predictive ability of the resulting models was evaluated against a test set of 8 compounds. The best QSAR models were further validated by leave one out technique as well as by the calculation of statistical parameters for the established theoretical models. Therefore, satisfactory relationships between antifungal activity and molecular descriptors were found. QSAR analysis reveals that lipophilicity descriptor (logP), dipole moment (DM) and surface area grid (SAG) govern the inhibitory activity of compounds studied against Saccharomyces cerevisiae.

  12. Quantitative structure-activity relationships and docking studies of calcitonin gene-related peptide antagonists.

    PubMed

    Kyani, Anahita; Mehrabian, Mohadeseh; Jenssen, Håvard

    2012-02-01

    Defining the role of calcitonin gene-related peptide in migraine pathogenesis could lead to the application of calcitonin gene-related peptide antagonists as novel migraine therapeutics. In this work, quantitative structure-activity relationship modeling of biological activities of a large range of calcitonin gene-related peptide antagonists was performed using a panel of physicochemical descriptors. The computational studies evaluated different variable selection techniques and demonstrated shuffling stepwise multiple linear regression to be superior over genetic algorithm-multiple linear regression. The linear quantitative structure-activity relationship model revealed better statistical parameters of cross-validation in comparison with the non-linear support vector regression technique. Implementing only five peptide descriptors into this linear quantitative structure-activity relationship model resulted in an extremely robust and highly predictive model with calibration, leave-one-out and leave-20-out validation R(2) of 0.9194, 0.9103, and 0.9214, respectively. We performed docking of the most potent calcitonin gene-related peptide antagonists with the calcitonin gene-related peptide receptor and demonstrated that peptide antagonists act by blocking access to the peptide-binding cleft. We also demonstrated the direct contact of residues 28-37 of the calcitonin gene-related peptide antagonists with the receptor. These results are in agreement with the conclusions drawn from the quantitative structure-activity relationship model, indicating that both electrostatic and steric factors should be taken into account when designing novel calcitonin gene-related peptide antagonists. PMID:21974743

  13. Hierarchical longitudinal models of relationships in social networks

    PubMed Central

    Paul, Sudeshna; O’Malley, A. James

    2013-01-01

    Summary Motivated by the need to understand the dynamics of relationship formation and dissolution over time in real-world social networks we develop a new longitudinal model for transitions in the relationship status of pairs of individuals (“dyads”). We first specify a model for the relationship status of a single dyad and then extend it to account for important inter-dyad dependencies (e.g., transitivity – “a friend of a friend is a friend”) and heterogeneity. Model parameters are estimated using Bayesian analysis implemented via Markov chain Monte Carlo. We use the model to perform novel analyses of two diverse longitudinal friendship networks: an excerpt of the Teenage Friends and Lifestyle Study (a moderately sized network) and the Framingham Heart Study (FHS) (a large network). PMID:24729637

  14. Relationship between ankle stiffness structure and muscle activation.

    PubMed

    Lee, Hyunglae; Wang, Shuo; Hogan, Neville

    2012-01-01

    This paper presents a characterization of the structure of ankle stiffness under multiple levels of muscle activation and the relationship between them. A multi-variable impedance estimation method using a wearable ankle robot enabled clear identification of ankle stiffness structure in the space consisting of the sagittal and frontal planes. With visual feedback showing current and target muscle activation levels, all subjects could successfully maintain multiple target levels (5%∼30% of the maximum voluntary contraction level). Stiffness increased with muscle activation, but the increase was more pronounced in the dorsiflexion-plantarflexion direction than in the inversion-eversion direction, which resulted in a characteristic "peanut" shape. The relation between measured muscle activation level and ankle stiffness was evaluated. All subjects showed a highly linear relation not only for the two principal axis directions of the ankle, i.e., dorsiflexion-plantarflexion and inversion-eversion, but also for the average stiffness value of all directions. These major findings were consistent both for the tibialis anterior and triceps surae activation.

  15. Thapsigargin, Origin, Chemistry, Structure-Activity Relationships and Prodrug Development.

    PubMed

    Quynh Doan, Nhu Thi; Christensen, Soren Brogger

    2015-01-01

    Thapsigargin was originally isolated from the roots of the Mediterranean umbelliferous plant Thapsia garganica in order to characterize the skin irritant principle. Characteristic chemical properties and semi-syntheses are reviewed. The biological activity was related to the subnanomolar affinity for the sarco/endoplasmic reticulum calcium ATPase. Prolonged inhibition of the pump afforded collapse of the calcium homeostasis and eventually apoptosis. Structure-activity relationships enabled design of an equipotent analogue containing a linker. Conjugation of the analogue containing the linker with peptides, which only are substrates for either prostate specific antigen (PSA) or prostate specific membrane antigen (PSMA) enabled design of prodrugs targeting a number of cancer diseases including prostate cancer (G115) and hepatocellular carcinoma (G202). Prodrug G202 has under the name of mipsagargin in phase II clinical trials shown promising properties against hepatocellular carcinoma.

  16. Possible Relationship of the Solar Activity and Earthquakes

    NASA Astrophysics Data System (ADS)

    Gonzalez-Trejo, J. I.; Cervantes, F.; Real-Ramírez, C. A.; Hoyos-Reyes, L. F.; Miranda-Tello, R.; Area de Sistemas Computacionales

    2013-05-01

    Several authors have recently argued that there is a relationship between solar activity and big earthquakes. This work compares Dst index fluctuations along 2012 and 2013, with the earthquake activity near La Paz, Baja California, Mexico. The earthquakes measurements at this place were divided according its deep focus. It was observed that the frequency of the deeper earthquakes increases shortly after considerable fluctuations in the Dst index are registered. We assume that the number of deep earthquakes increases because the interaction of the tectonic plate below that place and the tectonic plates in contact with it increases. This work also shows that the frequency of shallowest minor and light earthquakes increases shortly before a strongest earthquake takes place in the vicinity.

  17. Thapsigargin, Origin, Chemistry, Structure-Activity Relationships and Prodrug Development.

    PubMed

    Quynh Doan, Nhu Thi; Christensen, Soren Brogger

    2015-01-01

    Thapsigargin was originally isolated from the roots of the Mediterranean umbelliferous plant Thapsia garganica in order to characterize the skin irritant principle. Characteristic chemical properties and semi-syntheses are reviewed. The biological activity was related to the subnanomolar affinity for the sarco/endoplasmic reticulum calcium ATPase. Prolonged inhibition of the pump afforded collapse of the calcium homeostasis and eventually apoptosis. Structure-activity relationships enabled design of an equipotent analogue containing a linker. Conjugation of the analogue containing the linker with peptides, which only are substrates for either prostate specific antigen (PSA) or prostate specific membrane antigen (PSMA) enabled design of prodrugs targeting a number of cancer diseases including prostate cancer (G115) and hepatocellular carcinoma (G202). Prodrug G202 has under the name of mipsagargin in phase II clinical trials shown promising properties against hepatocellular carcinoma. PMID:26429715

  18. Anthocyanidins inhibit activator protein 1 activity and cell transformation: structure-activity relationship and molecular mechanisms.

    PubMed

    Hou, De-Xing; Kai, Keiko; Li, Jian-Jian; Lin, Shigang; Terahara, Norihiko; Wakamatsu, Mika; Fujii, Makoto; Young, Mattew R; Colburn, Nancy

    2004-01-01

    Anthocyanins are the chemical components that give the intense color to many fruits and vegetables, such as blueberries, red cabbages and purple sweet potatoes. Extensive studies have indicated that anthocyanins have strong antioxidant activities. To investigate the mechanism of anthocyanidins as an anticancer food source, six kinds of anthocyanidins representing the aglycons of most anthocyanins, were used to examine their effects on tumor promotion in mouse JB6 cells, a validated model for screening cancer chemopreventive agents and elucidating the molecular mechanisms. Of the six anthocyanins tested, only those with an ortho-dihydroxyphenyl structure on the B-ring suppressed 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced cell transformation and activator protein-1 transactivation, suggesting that the ortho-dihydroxyphenyl may contribute to the inhibitory action. Delphinidin, but not peonidin, blocked the phosphorylation of protein kinases in the extracellular signal-regulated protein kinase (ERK) pathway at early times and the c-Jun N-terminal kinase (JNK) signaling pathway at later times. p38 kinase was not inhibited by delphinidin. Furthermore, two mitogen-activated protein kinase (MAPK) specific inhibitors (SP600125 for JNK and UO126 for ERK) could specifically block the activation of JNK and ERK and cell transformation. Those results demonstrate that anthocyanidins contribute to the inhibition of tumorigenesis by blocking activation of the MAPK pathway. These findings provide the first molecular basis for the anticarcinogenic action of anthocyanidins. PMID:14514663

  19. Anthocyanidins inhibit activator protein 1 activity and cell transformation: structure-activity relationship and molecular mechanisms.

    PubMed

    Hou, De-Xing; Kai, Keiko; Li, Jian-Jian; Lin, Shigang; Terahara, Norihiko; Wakamatsu, Mika; Fujii, Makoto; Young, Mattew R; Colburn, Nancy

    2004-01-01

    Anthocyanins are the chemical components that give the intense color to many fruits and vegetables, such as blueberries, red cabbages and purple sweet potatoes. Extensive studies have indicated that anthocyanins have strong antioxidant activities. To investigate the mechanism of anthocyanidins as an anticancer food source, six kinds of anthocyanidins representing the aglycons of most anthocyanins, were used to examine their effects on tumor promotion in mouse JB6 cells, a validated model for screening cancer chemopreventive agents and elucidating the molecular mechanisms. Of the six anthocyanins tested, only those with an ortho-dihydroxyphenyl structure on the B-ring suppressed 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced cell transformation and activator protein-1 transactivation, suggesting that the ortho-dihydroxyphenyl may contribute to the inhibitory action. Delphinidin, but not peonidin, blocked the phosphorylation of protein kinases in the extracellular signal-regulated protein kinase (ERK) pathway at early times and the c-Jun N-terminal kinase (JNK) signaling pathway at later times. p38 kinase was not inhibited by delphinidin. Furthermore, two mitogen-activated protein kinase (MAPK) specific inhibitors (SP600125 for JNK and UO126 for ERK) could specifically block the activation of JNK and ERK and cell transformation. Those results demonstrate that anthocyanidins contribute to the inhibition of tumorigenesis by blocking activation of the MAPK pathway. These findings provide the first molecular basis for the anticarcinogenic action of anthocyanidins.

  20. Passion for an activity and quality of interpersonal relationships: the mediating role of emotions.

    PubMed

    Philippe, Frederick L; Vallerand, Robert J; Houlfort, Nathalie; Lavigne, Geneviève L; Donahue, Eric G

    2010-06-01

    Our purpose in this research was to investigate the role of passion (Vallerand et al., 2003) for a given activity in the quality of interpersonal relationships experienced within the context of that activity in 4 studies. Study 1 demonstrated that a harmonious passion was positively associated with the quality of interpersonal relationships within the context of the passionate activity, whereas an obsessive passion was unrelated to it. Furthermore, in line with the broaden-and-build theory (Fredrickson, 2001), results also showed that positive emotions experienced at work fully mediated the relation between harmonious passion and quality of interpersonal relationships. Obsessive passion was not associated with positive emotions. Study 2 replicated the results from Study 1 while controlling for trait extraversion. Also, in Study 2, we examined the negative mediating role of negative emotions between obsessive passion and quality of interpersonal relationships. Finally, Studies 3 and 4 replicated the results of Study 2 with prospective designs and with objective ratings of interpersonal relationships quality. Implications for the dualistic model of passion and the broaden-and-build theory are discussed.

  1. A computational quantitative structure-activity relationship study of carbamate anticonvulsants using quantum pharmacological methods.

    PubMed

    Knight, J L; Weaver, D F

    1998-10-01

    A pattern recognition quantitative structure-activity relationship (QSAR) study has been performed to determine the molecular features of carbamate anticonvulsants which influence biological activity. Although carbamates, such as felbamate, have been used to treat epilepsy, their mechanisms of efficacy and toxicity are not completely understood. Quantum and classical mechanics calculations have been exploited to describe 46 carbamate drugs. Employing a principal component analysis and multiple linear regression calculations, five crucial structural descriptors were identified which directly relate to the bioactivity of the carbamate family. With the resulting mathematical model, the biological activity of carbamate analogues can be predicted with 85-90% accuracy.

  2. Probabilistic constitutive relationships for cyclic material strength models

    NASA Technical Reports Server (NTRS)

    Boyce, L.; Chamis, C. C.

    1988-01-01

    A methodology is developed that provides a probabilistic treatment for the lifetime of structural components of aerospace propulsion systems subjected to fatigue. Material strength degradation models, based on primitive variables, include both a fatigue strength reduction model and a fatigue crack growth model. Probabilistic analysis is based on simulation, and both maximum entropy and maximum penalized likelihood methods are used for the generation of probability density functions. The resulting constitutive relationships are included in several computer programs.

  3. Design, synthesis and exploring the quantitative structure-activity relationship of some antioxidant flavonoid analogues.

    PubMed

    Das, Sreeparna; Mitra, Indrani; Batuta, Shaikh; Niharul Alam, Md; Roy, Kunal; Begum, Naznin Ara

    2014-11-01

    A series of flavonoid analogues were synthesized and screened for the in vitro antioxidant activity through their ability to quench 1,1-diphenyl-2-picryl hydrazyl (DPPH) radical. The activity of these compounds, measured in comparison to the well-known standard antioxidants (29-32), their precursors (38-42) and other bioactive moieties (38-42) resembling partially the flavone skeleton was analyzed further to develop Quantitative Structure-Activity Relationship (QSAR) models using the Genetic Function Approximation (GFA) technique. Based on the essential structural requirements predicted by the QSAR models, some analogues were designed, synthesized and tested for activity. The predicted and experimental activities of these compounds were well correlated. Flavone analogue 20 was found to be the most potent antioxidant.

  4. Exploring Third-Grade Student Model-Based Explanations about Plant Relationships within an Ecosystem

    NASA Astrophysics Data System (ADS)

    Zangori, Laura; Forbes, Cory T.

    2015-12-01

    Elementary students should have opportunities to develop scientific models to reason and build understanding about how and why plants depend on relationships within an ecosystem for growth and survival. However, scientific modeling practices are rarely included within elementary science learning environments and disciplinary content is often treated as discrete pieces separate from scientific practice. Elementary students have few, if any, opportunities to reason about how individual organisms, such as plants, hold critical relationships with their surrounding environment. The purpose of this design-based research study is to build a learning performance to identify and explore the third-grade students' baseline understanding of and their reasoning about plant-ecosystem relationships when engaged in the practices of modeling. The developed learning performance integrated scientific content and core scientific activity to identify and measure how students build knowledge about the role of plants in ecosystems through the practices of modeling. Our findings indicate that the third-grade students' ideas about plant growth include abiotic and biotic relationships. Further, they used their models to reason about how and why these relationships were necessary to maintain plant stasis. However, while the majority of the third-grade students were able to identify and reason about plant-abiotic relationships, a much smaller group reasoned about plant-abiotic-animal relationships. Implications from the study suggest that modeling serves as a tool to support elementary students in reasoning about system relationships, but they require greater curricular and instructional support in conceptualizing how and why ecosystem relationships are necessary for plant growth and development. This paper is based on data from a doctoral dissertation. An earlier version of this paper was presented at the 2015 international conference for the National Association for Research in Science

  5. Personality, Relationship Conflict, and Teamwork-Related Mental Models

    PubMed Central

    Vîrgă, Delia; CurŞeu, Petru Lucian; Maricuţoiu, Laurenţiu; Sava, Florin A.; Macsinga, Irina; Măgurean, Silvia

    2014-01-01

    This study seeks to explore whether neuroticism, agreeableness, and conscientiousness moderate the influence of relationship conflict experienced in groups on changes in group members' evaluative cognitions related to teamwork quality (teamwork-related mental models). Data from 216 students, nested in 48 groups were analyzed using a multilevel modeling approach. Our results show that the experience of relationship conflict leads to a negative shift from the pre-task to the post-task teamwork-related mental models. Moreover, the results indicate that conscientiousness buffered the negative association between relationship conflict and the change in teamwork-related mental models. Our results did not support the hypothesized moderating effect of agreeableness and show that the detrimental effect of relationship conflict on the shift in teamwork-related mental models is accentuated for group members scoring low rather than high on neuroticism. These findings open new research venues for exploring the association between personality, coping styles and change in teamwork-related mental models. PMID:25372143

  6. Personality, relationship conflict, and teamwork-related mental models.

    PubMed

    Vîrgă, Delia; Curşeu, Petru Lucian; CurŞeu, Petru Lucian; Maricuţoiu, Laurenţiu; Sava, Florin A; Macsinga, Irina; Măgurean, Silvia

    2014-01-01

    This study seeks to explore whether neuroticism, agreeableness, and conscientiousness moderate the influence of relationship conflict experienced in groups on changes in group members' evaluative cognitions related to teamwork quality (teamwork-related mental models). Data from 216 students, nested in 48 groups were analyzed using a multilevel modeling approach. Our results show that the experience of relationship conflict leads to a negative shift from the pre-task to the post-task teamwork-related mental models. Moreover, the results indicate that conscientiousness buffered the negative association between relationship conflict and the change in teamwork-related mental models. Our results did not support the hypothesized moderating effect of agreeableness and show that the detrimental effect of relationship conflict on the shift in teamwork-related mental models is accentuated for group members scoring low rather than high on neuroticism. These findings open new research venues for exploring the association between personality, coping styles and change in teamwork-related mental models.

  7. Method for the evaluation of structure-activity relationship information associated with coordinated activity cliffs.

    PubMed

    Dimova, Dilyana; Stumpfe, Dagmar; Bajorath, Jürgen

    2014-08-14

    Activity cliffs are generally defined as pairs of active compounds having a large difference in potency. Although this definition of activity cliffs focuses on compound pairs, the vast majority of cliffs are formed in a coordinated manner. This means that multiple highly and weakly potent compounds form series of activity cliffs, which often overlap. In activity cliff networks, coordinated cliffs emerge as disjoint activity cliff clusters. Recently, we have identified all cliff clusters from current bioactive compounds and analyzed their topologies. For structure-activity relationship (SAR) analysis, activity cliff clusters are of high interest, since they contain more SAR information than cliffs that are individually considered. For medicinal chemistry applications, a key question becomes how to best extract SAR information from activity cliff clusters. This represents a challenging problem, given the complexity of many activity cliff configurations. Herein we introduce a generally applicable methodology to organize activity cliff clusters on the basis of structural relationships, prioritize clusters, and systematically extract SAR information from them. PMID:25014781

  8. The current status and future applicability of quantitative structure-activity relationships (QSARs) in predicting toxicity.

    PubMed

    Cronin, Mark T D

    2002-12-01

    The current status of quantitative structure-activity relationships (QSARs) in predicting toxicity is assessed. Widespread use of these methods to predict toxicity from chemical structure is possible, both by industry to develop new compounds, and also by regulatory agencies. The current use of QSARs is restricted by the lack of suitable toxicity data available for modelling, the suitability of simplistic modelling approaches for the prediction of certain endpoints, and the poor definition and utilisation of the applicability domain of models. Suggestions to resolve these issues are made.

  9. 49 CFR 173.434 - Activity-mass relationships for uranium and natural thorium.

    Code of Federal Regulations, 2013 CFR

    2013-10-01

    ... 49 Transportation 2 2013-10-01 2013-10-01 false Activity-mass relationships for uranium and....434 Activity-mass relationships for uranium and natural thorium. The table of activity-mass relationships for uranium and natural thorium are as follows: Thorium and uranium enrichment 1(Wt% 235 U...

  10. 49 CFR 173.434 - Activity-mass relationships for uranium and natural thorium.

    Code of Federal Regulations, 2012 CFR

    2012-10-01

    ... 49 Transportation 2 2012-10-01 2012-10-01 false Activity-mass relationships for uranium and....434 Activity-mass relationships for uranium and natural thorium. The table of activity-mass relationships for uranium and natural thorium are as follows: Thorium and uranium enrichment 1(Wt% 235 U...

  11. 49 CFR 173.434 - Activity-mass relationships for uranium and natural thorium.

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... 49 Transportation 2 2011-10-01 2011-10-01 false Activity-mass relationships for uranium and....434 Activity-mass relationships for uranium and natural thorium. The table of activity-mass relationships for uranium and natural thorium are as follows: Thorium and uranium enrichment 1(Wt% 235 U...

  12. 49 CFR 173.434 - Activity-mass relationships for uranium and natural thorium.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... 49 Transportation 2 2010-10-01 2010-10-01 false Activity-mass relationships for uranium and....434 Activity-mass relationships for uranium and natural thorium. The table of activity-mass relationships for uranium and natural thorium are as follows: Thorium and uranium enrichment 1(Wt% 235 U...

  13. 49 CFR 173.434 - Activity-mass relationships for uranium and natural thorium.

    Code of Federal Regulations, 2014 CFR

    2014-10-01

    ... 49 Transportation 2 2014-10-01 2014-10-01 false Activity-mass relationships for uranium and....434 Activity-mass relationships for uranium and natural thorium. The table of activity-mass relationships for uranium and natural thorium are as follows: Thorium and uranium enrichment 1(Wt% 235 U...

  14. Trypanocidal nitroimidazole derivatives: relationships among chemical structure and genotoxic activity.

    PubMed

    Buschini, Annamaria; Giordani, Federica; de Albuquerque, Cristina Northfleet; Pellacani, Claudia; Pelosi, Giorgio; Rossi, Carlo; Zucchi, Tânia Maria Araújo Domingues; Poli, Paola

    2007-05-15

    Human American trypanosomiasis is resurgent in Latin Americans, and new drugs are urgently required as current medications suffer from a number of drawbacks. Some nitroheterocycles have been demonstrated to exert a potent activity against trypanosomes. However, host toxicity issues halted their development as trypanocides. As part of the efforts to develop new compounds in order to treat parasitic infections, it is important to define their structure-activity relationship. In this study, 5-nitromegazol and two of its analogues, 4-nitromegazol, and 1-methyl-5-nitro-2-imidazolecarboxaldehyde 5-nitroimidazole-thiosemicarbazone, were tested and compared for in vitro induction of DNA damage in human leukocytes by the comet assay, performed at different pHs to better identify the types of damage. Specific oxidatively generated damage to DNA was also measured by using the comet assay with endonucleases. DNA damage was found in 5-nitromegazol-treated cells: oxidative stress appeared as the main source of DNA damage. 4-Nitromegazol did not produce any significant effect, thus confirming that 4-nitroimidazoles isomers have no important biological activity. The 5-nitroimidazole-thiosemicarbazone induced DNA damage with a higher efficiency than 5-nitromegazol. The central role in the reduction process played by the acidic hydrazine proton present in the thiosemicarbazone group but not in the cyclic (thiadiazole) form can contribute to rationalise our results. Given its versatility, thiosemicarbazone moiety could be involved in different reactions with nitrogenous bases (nucleophilic and/or electrophilic attacks).

  15. Synthesis and Structural Activity Relationship Study of Antitubercular Carboxamides

    PubMed Central

    Ugwu, D. I.; Ezema, B. E.; Eze, F. U.; Ugwuja, D. I.

    2014-01-01

    The unusual structure and chemical composition of the mycobacterial cell wall, the tedious duration of therapy, and resistance developed by the microorganism have made the recurrence of the disease multidrug resistance and extensive or extreme drug resistance. The prevalence of tuberculosis in synergy with HIV/AIDS epidemic augments the risk of developing the disease by 100-fold. The need to synthesize new drugs that will shorten the total duration of effective treatment and/or significantly reduce the dosage taken under DOTS supervision, improve on the treatment of multidrug-resistant tuberculosis which defies the treatment with isoniazid and rifampicin, and provide effective treatment for latent TB infections which is essential for eliminating tuberculosis prompted this review. In this review, we considered the synthesis and structure activity relationship study of carboxamide derivatives with antitubercular potential. PMID:25610646

  16. Capsaicin and its analogues: structure-activity relationship study.

    PubMed

    Huang, X-F; Xue, J-Y; Jiang, A-Q; Zhu, H-L

    2013-01-01

    Capsaicin, the main ingredient responsible for the hot pungent taste of chilli peppers, is an alkaloid found in the Capsicum family. Capsaicin was traditionally used for muscular pain, headaches, to improve circulation and for its gastrointestinal protective effects. It was also commonly added to herbal formulations because it acts as a catalyst for other herbs and aids in their absorption. In addition, capsaicin and other capsaicinoid compounds showed strong evidence of having promising potential in the fight against many types of cancer. The mechanism of action of capsaicin has been extensively studied over the past decade. It has been established that capsaicin binds to the transient receptor potential vanilloid 1 receptor which was expressed predominantly by sensory neurons. And many analogues of capsaicin have been synthesized and evaluated for diverse bioactivities. In this review, we will attempt to summarize the biology and structure-activity relationship of capsaicinoids.

  17. The relationships between active extensibility, and passive and active stiffness of the knee flexors.

    PubMed

    Blackburn, J Troy; Padua, Darin A; Riemann, Bryan L; Guskiewicz, Kevin M

    2004-12-01

    Insufficient active knee flexor stiffness may predispose the anterior cruciate ligament to injury. Insufficient passive stiffness may result in insufficient active stiffness. Similarly, higher levels of musculotendinous extensibility may inhibit active and passive muscle stiffness, potentially contributing to an increased risk of injury. The literature is both limited and inconsistent concerning relationships between extensibility, passive stiffness, and active stiffness. Extensibility was measured as the maximal active knee extension angle from a supine position with the hip flexed to 90 degrees . Passive stiffness was calculated as the slope of the moment-angle curve resulting from passive knee extension. Active stiffness was assessed via acceleration associated with damped oscillatory motion about the knee. Stepwise multiple regression indicated that passive stiffness accounted for 25% of active muscle stiffness variance. The linear combination of extensibility and passive stiffness explained only 2% more variance compared to passive stiffness alone. Musculotendinous extensibility was moderately related to passive muscle stiffness, and weakly related to active muscle stiffness. The moderate relationship observed between active and passive stiffness emphasizes the dependence of active muscle stiffness on cross-bridge formation, and the relatively smaller contribution from parallel elastic tissues. Additionally, heightened extensibility does not appear to be a predisposing factor for reduced muscle stiffness. PMID:15491843

  18. Antioxidant, cytotoxic activities, and structure-activity relationship of gallic acid-based indole derivatives.

    PubMed

    Khaledi, Hamid; Alhadi, Abeer A; Yehye, Wagee A; Ali, Hapipah Mohd; Abdulla, Mahmood A; Hassandarvish, Pouya

    2011-11-01

    A new series of gallic hydrazones containing an indole moiety was synthesized through the reaction of gallic hydrazide and different indole carboxaldehydes. Their antioxidant activities were determined on DPPH radical scavenging and inhibition of lipid peroxidation. The in-vitro cytotoxic activities of the compounds were evaluated against HCT-116 (human colon cancer cell line) and MCF-7 (estrogen-dependent human breast cancer cell line) by the MTT method. An attempt to correlate the biological results with their structural characteristics has been done. A limited positive structure activity relationship was found between cytotoxic and antioxidant activities.

  19. Structure activity relationship, cytotoxicity and evaluation of antioxidant activity of curcumin derivatives.

    PubMed

    Sahu, Pramod K; Sahu, Praveen K; Sahu, Puran L; Agarwal, Dau D

    2016-02-15

    Series of curcumin derivatives/analogues were designed and efficient method for synthesis thereof is described. All the synthesized compounds have been screened for their cytotoxicity and evaluated their antioxidant activity. Cytotoxicity effect has been evaluated against three cell lines Hep-G2, HCT-116 and QG-56 by MTT assay method. Structure activity relationship has revealed that particularly, compound 3c, (IC50 value 6.25 μM) has shown better cytotoxicity effect against three cell lines. According to results of SAR study, it was found that 4H-pyrimido[2,1-b]benzothiazole derivatives (2e and 2f), pyrazoles (3a, 3b, 3c and 3d) benzylidenes (4d) exhibited better antioxidant activity than curcumin. A correlation of structure and activities relationship of these compounds with respect to drug score profiles and other physico-chemical properties of drugs are described and verified experimentally. PMID:26810315

  20. Modeling Cytoskeletal Active Matter Systems

    NASA Astrophysics Data System (ADS)

    Blackwell, Robert

    Active networks of filamentous proteins and crosslinking motor proteins play a critical role in many important cellular processes. One of the most important microtubule-motor protein assemblies is the mitotic spindle, a self-organized active liquid-crystalline structure that forms during cell division and that ultimately separates chromosomes into two daughter cells. Although the spindle has been intensively studied for decades, the physical principles that govern its self-organization and function remain mysterious. To evolve a better understanding of spindle formation, structure, and dynamics, I investigate course-grained models of active liquid-crystalline networks composed of microtubules, modeled as hard spherocylinders, in diffusive equilibrium with a reservoir of active crosslinks, modeled as hookean springs that can adsorb to microtubules and and translocate at finite velocity along the microtubule axis. This model is investigated using a combination of brownian dynamics and kinetic monte carlo simulation. I have further refined this model to simulate spindle formation and kinetochore capture in the fission yeast S. pombe. I then make predictions for experimentally realizable perturbations in motor protein presence and function in S. pombe.

  1. Concepts of disability: the Activity Space Model.

    PubMed

    Kopec, J A

    1995-03-01

    This paper describes a new conceptual framework for functional assessment, the Activity Space Model (ASM). According to this model, functional impairments may lead to restrictions in an individual's activity space, a multidimensional space that represents human potential for activity. For each elementary ability, restrictions in the corresponding dimension of the activity space can be evaluated by deriving a difficulty curve that depicts the relationship between the level of performance and the psychophysical cost of activity. The effect of disease on daily functioning is explained in terms of a tradeoff between the psychophysical cost and the value of each act of behavior to the disabled individual. These two constructs are measured on the same scale and expressed in units of difficulty. The location of each task within the activity space in relation to the difficulty curve determines whether it will be performed or avoided at a given point in time. The ASM has both theoretical and practical implications. It offers a new, integrated perspective on disability and suggests new strategies for developing and evaluating functional assessment measures.

  2. Using avian radar to examine relationships among avian activity, bird strikes, and meteorological factors

    USGS Publications Warehouse

    Coates, Peter S.; Casazza, Michael L.; Halstead, Brian J.; Fleskes, Joseph P.; Laughlin, James A.

    2011-01-01

    Radar systems designed to detect avian activity at airfields are useful in understanding factors that influence the risk of bird and aircraft collisions (bird strikes). We used an avian radar system to measure avian activity at Beale Air Force Base, California, USA, during 2008 and 2009. We conducted a 2-part analysis to examine relationships among avian activity, bird strikes, and meteorological and time-dependent factors. We found that avian activity around the airfield was greater at times when bird strikes occurred than on average using a permutation resampling technique. Second, we developed generalized linear mixed models of an avian activity index (AAI). Variation in AAI was first explained by seasons that were based on average migration dates of birds at the study area. We then modeled AAI by those seasons to further explain variation by meteorological factors and daily light levels within a 24-hour period. In general, avian activity increased with decreased temperature, wind, visibility, precipitation, and increased humidity and cloud cover. These effects differed by season. For example, during the spring bird migration period, most avian activity occurred before sunrise at twilight hours on clear days with low winds, whereas during fall migration, substantial activity occurred after sunrise, and birds generally were more active at lower temperatures. We report parameter estimates (i.e., constants and coefficients) averaged across models and a relatively simple calculation for safety officers and wildlife managers to predict AAI and the relative risk of bird strike based on time, date, and meteorological values. We validated model predictability and assessed model fit. These analyses will be useful for general inference of avian activity and risk assessment efforts. Further investigation and ongoing data collection will refine these inference models and improve our understanding of factors that influence avian activity, which is necessary to inform

  3. Quantitative structure-activity relationship correlation between molecular structure and the Rayleigh enantiomeric enrichment factor.

    PubMed

    Jammer, S; Rizkov, D; Gelman, F; Lev, O

    2015-08-01

    It was recently demonstrated that under environmentally relevant conditions the Rayleigh equation is valid to describe the enantiomeric enrichment - conversion relationship, yielding a proportional constant called the enantiomeric enrichment factor, εER. In the present study we demonstrate a quantitative structure-activity relationship model (QSAR) that describes well the dependence of εER on molecular structure. The enantiomeric enrichment factor can be predicted by the linear Hansch model, which correlates biological activity with physicochemical properties. Enantioselective hydrolysis of sixteen derivatives of 2-(phenoxy)propionate (PPMs) have been analyzed during enzymatic degradation by lipases from Pseudomonas fluorescens (PFL), Pseudomonas cepacia (PCL), and Candida rugosa (CRL). In all cases the QSAR relationships were significant with R(2) values of 0.90-0.93, and showed high predictive abilities with internal and external validations providing QLOO(2) values of 0.85-0.87 and QExt(2) values of 0.8-0.91. Moreover, it is demonstrated that this model enables differentiation between enzymes with different binding site shapes. The enantioselectivity of PFL and PCL was dictated by electronic properties, whereas the enantioselectivity of CRL was determined by lipophilicity and steric factors. The predictive ability of the QSAR model demonstrated in the present study may serve as a helpful tool in environmental studies, assisting in source tracking of unstudied chiral compounds belonging to a well-studied homologous series.

  4. Testing a Theoretical Model of Immigration Transition and Physical Activity.

    PubMed

    Chang, Sun Ju; Im, Eun-Ok

    2015-01-01

    The purposes of the study were to develop a theoretical model to explain the relationships between immigration transition and midlife women's physical activity and test the relationships among the major variables of the model. A theoretical model, which was developed based on transitions theory and the midlife women's attitudes toward physical activity theory, consists of 4 major variables, including length of stay in the United States, country of birth, level of acculturation, and midlife women's physical activity. To test the theoretical model, a secondary analysis with data from 127 Hispanic women and 123 non-Hispanic (NH) Asian women in a national Internet study was used. Among the major variables of the model, length of stay in the United States was negatively associated with physical activity in Hispanic women. Level of acculturation in NH Asian women was positively correlated with women's physical activity. Country of birth and level of acculturation were significant factors that influenced physical activity in both Hispanic and NH Asian women. The findings support the theoretical model that was developed to examine relationships between immigration transition and physical activity; it shows that immigration transition can play an essential role in influencing health behaviors of immigrant populations in the United States. The NH theoretical model can be widely used in nursing practice and research that focus on immigrant women and their health behaviors. Health care providers need to consider the influences of immigration transition to promote immigrant women's physical activity. PMID:26502554

  5. Testing a Theoretical Model of Immigration Transition and Physical Activity.

    PubMed

    Chang, Sun Ju; Im, Eun-Ok

    2015-01-01

    The purposes of the study were to develop a theoretical model to explain the relationships between immigration transition and midlife women's physical activity and test the relationships among the major variables of the model. A theoretical model, which was developed based on transitions theory and the midlife women's attitudes toward physical activity theory, consists of 4 major variables, including length of stay in the United States, country of birth, level of acculturation, and midlife women's physical activity. To test the theoretical model, a secondary analysis with data from 127 Hispanic women and 123 non-Hispanic (NH) Asian women in a national Internet study was used. Among the major variables of the model, length of stay in the United States was negatively associated with physical activity in Hispanic women. Level of acculturation in NH Asian women was positively correlated with women's physical activity. Country of birth and level of acculturation were significant factors that influenced physical activity in both Hispanic and NH Asian women. The findings support the theoretical model that was developed to examine relationships between immigration transition and physical activity; it shows that immigration transition can play an essential role in influencing health behaviors of immigrant populations in the United States. The NH theoretical model can be widely used in nursing practice and research that focus on immigrant women and their health behaviors. Health care providers need to consider the influences of immigration transition to promote immigrant women's physical activity.

  6. Cultivating Knowledge Sharing through the Relationship Management Maturity Model

    ERIC Educational Resources Information Center

    Martin, Valerie A.; Hatzakis, Tally; Lycett, Mark; Macredie, Robert

    2005-01-01

    Purpose: The purpose of this paper is to present the development of the relationship management maturity model (RMMM), the output of an initiative aimed at bridging the gap between business units and the IT organisation. It does this through improving and assessing knowledge sharing between business and IT staff in Finco, a large financial…

  7. Modeling the Relationships between Subdimensions of Environmental Literacy

    ERIC Educational Resources Information Center

    Genc, Murat; Akilli, Mustafa

    2016-01-01

    The aim of this study is to demonstrate the relationships between subdimensions of environmental literacy using Structural Equation Modeling (SEM). The study was conducted by the analysis of students' answers to questionnaires data using SEM. Initially, Kaiser-Meyer-Olkin and Bartlett's tests were done to test appropriateness of subdimensions to…

  8. Modeling time-lagged reciprocal psychological empowerment-performance relationships.

    PubMed

    Maynard, M Travis; Luciano, Margaret M; D'Innocenzo, Lauren; Mathieu, John E; Dean, Matthew D

    2014-11-01

    Employee psychological empowerment is widely accepted as a means for organizations to compete in increasingly dynamic environments. Previous empirical research and meta-analyses have demonstrated that employee psychological empowerment is positively related to several attitudinal and behavioral outcomes including job performance. While this research positions psychological empowerment as an antecedent influencing such outcomes, a close examination of the literature reveals that this relationship is primarily based on cross-sectional research. Notably, evidence supporting the presumed benefits of empowerment has failed to account for potential reciprocal relationships and endogeneity effects. Accordingly, using a multiwave, time-lagged design, we model reciprocal relationships between psychological empowerment and job performance using a sample of 441 nurses from 5 hospitals. Incorporating temporal effects in a staggered research design and using structural equation modeling techniques, our findings provide support for the conventional positive correlation between empowerment and subsequent performance. Moreover, accounting for the temporal stability of variables over time, we found support for empowerment levels as positive influences on subsequent changes in performance. Finally, we also found support for the reciprocal relationship, as performance levels were shown to relate positively to changes in empowerment over time. Theoretical and practical implications of the reciprocal psychological empowerment-performance relationships are discussed. (PsycINFO Database Record (c) 2014 APA, all rights reserved).

  9. Modeling time-lagged reciprocal psychological empowerment-performance relationships.

    PubMed

    Maynard, M Travis; Luciano, Margaret M; D'Innocenzo, Lauren; Mathieu, John E; Dean, Matthew D

    2014-11-01

    Employee psychological empowerment is widely accepted as a means for organizations to compete in increasingly dynamic environments. Previous empirical research and meta-analyses have demonstrated that employee psychological empowerment is positively related to several attitudinal and behavioral outcomes including job performance. While this research positions psychological empowerment as an antecedent influencing such outcomes, a close examination of the literature reveals that this relationship is primarily based on cross-sectional research. Notably, evidence supporting the presumed benefits of empowerment has failed to account for potential reciprocal relationships and endogeneity effects. Accordingly, using a multiwave, time-lagged design, we model reciprocal relationships between psychological empowerment and job performance using a sample of 441 nurses from 5 hospitals. Incorporating temporal effects in a staggered research design and using structural equation modeling techniques, our findings provide support for the conventional positive correlation between empowerment and subsequent performance. Moreover, accounting for the temporal stability of variables over time, we found support for empowerment levels as positive influences on subsequent changes in performance. Finally, we also found support for the reciprocal relationship, as performance levels were shown to relate positively to changes in empowerment over time. Theoretical and practical implications of the reciprocal psychological empowerment-performance relationships are discussed. (PsycINFO Database Record (c) 2014 APA, all rights reserved). PMID:25111249

  10. Relationship duration moderates associations between attachment and relationship quality: meta-analytic support for the temporal adult romantic attachment model.

    PubMed

    Hadden, Benjamin W; Smith, C Veronica; Webster, Gregory D

    2014-02-01

    Although research has examined associations between attachment dimensions and relationship outcomes, theory has ignored how these associations change over time in adult romantic relationships. We proposed the Temporal Adult Romantic Attachment (TARA) model, which predicts that the negative associations between anxious and avoidant attachment on one hand and relationship satisfaction and commitment on the other will be more negative as relationship durations increase. Meta-analyses largely confirmed that negative associations between both insecure attachment dimensions and both relationship outcomes were more negative among longer relationship durations in cross-sectional samples. We also explored gender differences in these associations. The present review not only integrates the literature on adult attachment and romantic relationship satisfaction/commitment but also highlights the importance of relationship duration as a key moderator of the associations among these variables. We discuss the broad implications of these effects and our meta-analytic findings for the TARA model, attachment theory, and romantic relationships.

  11. The Tempo of Sexual Activity and Later Relationship Quality

    ERIC Educational Resources Information Center

    Sassler, Sharon; Addo, Fenaba R.; Lichter, Daniel T.

    2012-01-01

    Rapid sexual involvement may have adverse long-term implications for relationship quality. This study examined the tempo of sexual intimacy and subsequent relationship quality in a sample of married and cohabiting men and women. Data come from the Marital and Relationship Survey, which provides information on nearly 600 low- to moderate-income…

  12. Relationship between X(5) models and the interacting boson model

    SciTech Connect

    Barea, Jose; Arias, Jose M.; Garcia-Ramos, Jose Enrique

    2010-08-15

    The connections between the X(5) models [the original X(5) using an infinite square well, X(5)-{beta}{sup 8}, X(5)-{beta}{sup 6}, X(5)-{beta}{sup 4}, and X(5)-{beta}{sup 2}], based on particular solutions of the geometrical Bohr Hamiltonian with harmonic potential in the {gamma} degree of freedom, and the interacting boson model (IBM) are explored. This work is the natural extension of the work presented in Garcia-Ramos and Arias, Phys. Rev. C 77, 054307 (2008) for the E(5) models. For that purpose, a quite general one- and two-body IBM Hamiltonian is used and a numerical fit to the different X(5) model energies is performed; then the obtained wave functions are used to calculate B(E2) transition rates. It is shown that within the IBM one can reproduce well the results for energies and B(E2) transition rates obtained with all these X(5) models, although the agreement is not so impressive as for the E(5) models. From the fitted IBM parameters the corresponding energy surface can be extracted and, surprisingly, only the X(5) case corresponds in the moderately large N limit to an energy surface very close to the one expected for a critical point, whereas the rest of models are situated a little further away.

  13. A simple model clarifies the complicated relationships of complex networks

    NASA Astrophysics Data System (ADS)

    Zheng, Bojin; Wu, Hongrun; Kuang, Li; Qin, Jun; Du, Wenhua; Wang, Jianmin; Li, Deyi

    2014-08-01

    Real-world networks such as the Internet and WWW have many common traits. Until now, hundreds of models were proposed to characterize these traits for understanding the networks. Because different models used very different mechanisms, it is widely believed that these traits origin from different causes. However, we find that a simple model based on optimisation can produce many traits, including scale-free, small-world, ultra small-world, Delta-distribution, compact, fractal, regular and random networks. Moreover, by revising the proposed model, the community-structure networks are generated. By this model and the revised versions, the complicated relationships of complex networks are illustrated. The model brings a new universal perspective to the understanding of complex networks and provide a universal method to model complex networks from the viewpoint of optimisation.

  14. Synthesis, Structure-Activity Relationship, and Mechanistic Investigation of Lithocholic Acid Amphiphiles for Colon Cancer Therapy

    PubMed Central

    Bhargava, Priyanshu; Singh, Ashima; Motiani, Rajender K.; Shyam, Radhey; Sreekanth, Vedagopuram; Sengupta, Sagar; Bajaj, Avinash

    2014-01-01

    We report a structure-activity relationship of lithocholic acid amphiphiles for their anticancer activities against colon cancer. We synthesized ten cationic amphiphiles differing in nature of cationic charged head groups using lithocholic acid. We observed that anticancer activities of these amphiphiles against colon cancer cell lines are contingent on nature of charged head group. Lithocholic acid based amphiphile possessing piperidine head group (LCA-PIP1) is ~10 times more cytotoxic as compared to its precursor. Biochemical studies revealed that enhanced activity of LCA-PIP1 as compared to lithocholic acid is due to greater activation of apoptosis.LCA-PIP1 induces sub G0 arrest and causes cleavage of caspases. A single dose of lithocholic acid-piperidine derivative is enough to reduce the tumor burden by 75% in tumor xenograft model. PMID:25685308

  15. Structure-activity relationships for selected fragrance allergens.

    PubMed

    Patlewicz, G Y; Wright, Z M; Basketter, D A; Pease, C K; Lepoittevin, J-P; Arnau, E Giménez

    2002-10-01

    Fragrance substances represent a very diverse group of chemicals, a proportion of them providing not only desirable aroma characteristics, but also being associated with adverse effects, notably the ability to cause allergic reactions in the skin. However, efforts to find substitute materials are hampered by the need to undertake animal testing to evaluate both the presence and the degree of skin sensitization hazard. One potential route to avoid such testing is to understand the relationships between chemical structure and skin sensitization. In the present work we have evaluated two groups of fragrance chemicals, saturated aldehydes (aryl substituted and aliphatic aldehydes) and alpha,beta-unsaturated aldehydes. Data on their skin sensitization potency defined using the local lymph node assay has been evaluated in relation to their physicochemical properties. The initial outcome has been consistent with the concept that alpha,beta-unsaturated aldehydes react largely via Michael addition, whilst the group of saturated aldehydes form Schiff bases with proteins. Simple models of chemical reactivity based on these mechanisms suggest that it may be possible to predict allergenic potency. Accordingly, the evaluation of an additional group of similar aldehydes is now underway to assess the robustness of these models, with some emphasis being based on ensuring a wider spread of chemical reactivity.

  16. Structural interpretation of activity cliffs revealed by systematic analysis of structure-activity relationships in analog series.

    PubMed

    Sisay, Mihiret T; Peltason, Lisa; Bajorath, Jürgen

    2009-10-01

    Discontinuity in structure-activity relationships (SARs) is caused by so-called activity cliffs and represents one of the major caveats in SAR modeling and lead optimization. At activity cliffs, small structural modifications of compounds lead to substantial differences in potency that are essentially unpredictable using quantitative structure-activity relationship (QSAR) methods. In order to better understand SAR discontinuity at the molecular level of detail, we have analyzed different compound series in combinatorial analog graphs and determined substitution patterns that introduce activity cliffs of varying magnitude. So identified SAR determinants were then analyzed on the basis of complex crystal structures to enable a structural interpretation of SAR discontinuity and underlying activity cliffs. In some instances, SAR discontinuity detected within analog series could be well rationalized on the basis of structural data, whereas in others a structural explanation was not possible. This reflects the intrinsic complexity of small molecule SARs and suggests that the analysis of short-range receptor-ligand interactions seen in X-ray structures is insufficient to comprehensively account for SAR discontinuity. However, in other cases, SAR information extracted from ligands was incomplete but could be deduced taking X-ray data into account. Thus, taken together, these findings illustrate the complementarity of ligand-based SAR analysis and structural information. PMID:19761254

  17. Modeling Activities in Earth Science

    NASA Astrophysics Data System (ADS)

    Malone, Kathy

    2014-05-01

    Students usually find science to be quite abstract. This is especially true of disciplines like Earth Science where it is difficult for the students to conduct and design hands-on experiments in areas such as Plate Tectonics that would allow them to develop predictive models. In the United States the new Next Generation Science Standards explicitly requires students to experience the science disciplines via modeling based activities. This poster presentation will discuss an activity that demonstrates how modeling, plate tectonics and student discourse converge in the earth science classroom. The activities featured on the poster will include using cardboard and shaving cream to demonstrate convergent plate boundaries, a Milky Way candy bar to demonstrate divergent boundaries and silly putty to demonstrate a strike slip boundary. I will discuss how students report back to the group about the findings from the lab and the techniques that can be used to heighten the student discourse. The activities outlined in this poster were originally designed for a middle school Earth Science class by Suzi Shoemaker for a graduate thesis at Arizona State University.

  18. Improving quantitative structure-activity relationships through multiobjective optimization.

    PubMed

    Nicolotti, Orazio; Giangreco, Ilenia; Miscioscia, Teresa Fabiola; Carotti, Angelo

    2009-10-01

    A multiobjective optimization algorithm was proposed for the automated integration of structure- and ligand-based molecular design. Driven by a genetic algorithm, the herein proposed approach enabled the detection of a number of trade-off QSAR models accounting simultaneously for two independent objectives. The first was biased toward best regressions among docking scores and biological affinities; the second minimized the atom displacements from a properly established crystal-based binding topology. Based on the concept of dominance, 3D QSAR equivalent models profiled the Pareto frontier and were, thus, designated as nondominated solutions of the search space. K-means clustering was, then, operated to select a representative subset of the available trade-off models. These were effectively subjected to GRID/GOLPE analyses for quantitatively featuring molecular determinants of ligand binding affinity. More specifically, it was demonstrated that a) diverse binding conformations occurred on the basis of the ligand ability to profitably contact different part of protein binding site; b) enzyme selectivity was better approached and interpreted by combining diverse equivalent models; and c) trade-off models were successful and even better than docking virtual screening, in retrieving at high sensitivity active hits from a large pool of chemically similar decoys. The approach was tested on a large series, very well-known to QSAR practitioners, of 3-amidinophenylalanine inhibitors of thrombin and trypsin, two serine proteases having rather different biological actions despite a high sequence similarity. PMID:19785453

  19. Structure–Activity Relationship for the 4(3H)-Quinazolinone Antibacterials

    PubMed Central

    2016-01-01

    We recently reported on the discovery of a novel antibacterial (2) with a 4(3H)-quinazolinone core. This discovery was made by in silico screening of 1.2 million compounds for binding to a penicillin-binding protein and the subsequent demonstration of antibacterial activity against Staphylococcus aureus. The first structure–activity relationship for this antibacterial scaffold is explored in this report with evaluation of 77 variants of the structural class. Eleven promising compounds were further evaluated for in vitro toxicity, pharmacokinetics, and efficacy in a mouse peritonitis model of infection, which led to the discovery of compound 27. This new quinazolinone has potent activity against methicillin-resistant (MRSA) strains, low clearance, oral bioavailability and shows efficacy in a mouse neutropenic thigh infection model. PMID:27088777

  20. Antibacterial activity of xanthones from Garcinia mangostana (L.) and their structure-activity relationship studies.

    PubMed

    Dharmaratne, H R W; Sakagami, Yoshikazu; Piyasena, K G P; Thevanesam, Vasanthi

    2013-01-01

    Antibacterial activities of prenylated xanthones from Garcinia mangostana and their synthetic analogues were investigated, and their structure-activity relationships have been studied. γ-Mangostin has shown antibacterial activity against methicillin-resistant Staphylococcus aureus (MRSA), methicillin sensitive Staphylococcus aureus (MSSA), vancomycin-resistant Enterococcus (VRE) and vancomycin-sensitive Enterococcus (VSE) strains at MICs 3.13, 6.25, 6.25 and 6.25 µg mL(-1), respectively. In these experiments, gentamicin was used as the positive control. Further, some analogues of γ-mangostin and α-mangostin were synthesised and their activity was tested against MRSA and VRE strains. The analysis of the bioassay results above indicated that, the combination of C-6 and C-3 hydroxyl groups along with the prenyl side chain at C-2 in the 1,3,6,7-tetraoxygenated xanthones from G. mangostana is essential to have a high antibacterial activity.

  1. The structure-activity relationship in herbicidal monosubstituted sulfonylureas

    SciTech Connect

    Li, Zheng-Ming; Ma, Yi; Guddat, Luke; Cheng, Pei-Quan; Wang, Jian-Guo; Pang, Siew S; Dong, Yu-Hui; Lai, Cheng-Ming; Wang, Ling-Xiu; Jia, Guo-Feng; Li, Yong-Hong; Wang, Su-Hua; Liu, Jie; Zhao, Wei-Guang; Wang, Bao-Lei

    2012-05-24

    The herbicide sulfonylurea (SU) belongs to one of the most important class of herbicides worldwide. It is well known for its ecofriendly, extreme low toxicity towards mammals and ultralow dosage application. The original inventor, G Levitt, set out structure-activity relationship (SAR) guidelines for SU structural design to attain superhigh bioactivity. A new approach to SU molecular design has been developed. After the analysis of scores of SU products by X-ray diffraction methodology and after greenhouse herbicidal screening of 900 novel SU structures synthesized in the authors laboratory, it was found that several SU structures containing a monosubstituted pyrimidine moiety retain excellent herbicidal characteristics, which has led to partial revision of the Levitt guidelines. Among the novel SU molecules, monosulfuron and monosulfuron-ester have been developed into two new herbicides that have been officially approved for field application and applied in millet and wheat fields in China. A systematic structural study of the new substrate-target complex and the relative mode of action in comparison with conventional SU has been carried out. A new mode of action has been postulated.

  2. Structure-Activity Relationship Study of Hydroxycoumarins and Mushroom Tyrosinase.

    PubMed

    Asthana, Shailendra; Zucca, Paolo; Vargiu, Attilio V; Sanjust, Enrico; Ruggerone, Paolo; Rescigno, Antonio

    2015-08-19

    The structure-activity relationships of four hydroxycoumarins, two with the hydroxyl group on the aromatic ring of the molecule and two with the hydroxyl group replacing hydrogen of the pyrone ring, and their interactions with mushroom tyrosinase were studied. These compounds displayed different behaviors upon action of the enzyme. The two compounds, ar-hydroxylated 6-hydroxycoumarin and 7-hydroxycoumarin, were both weak substrates of the enzyme. Interestingly, in both cases, the product of the catalysis was the 6,7-hydroxycoumarin, although 5,6- and 7,8-isomers could also theoretically be formed. Additionally, both were able to reduce the formation of dopachrome when tyrosinase acted on its typical substrate, L-tyrosine. Although none of the compounds that contained a hydroxyl group on the pyrone ring were substrates of tyrosinase, the 3-hydroxycoumarin was a potent inhibitor of the enzyme, and the 4-hydroxycoumarin was not an inhibitor. These results were compared with those obtained by in silico molecular docking predictions to obtain potentially useful information for the synthesis of new coumarin-based inhibitors that resemble the structure of the 3-hydroxycoumarin.

  3. Structure activity relationships to assess new chemicals under TSCA

    SciTech Connect

    Auletta, A.E.

    1990-12-31

    Under Section 5 of the Toxic Substances Control Act (TSCA), manufacturers must notify the US Environmental Protection Agency (EPA) 90 days before manufacturing, processing, or importing a new chemical substance. This is referred to as a premanufacture notice (PMN). The PMN must contain certain information including chemical identity, production volume, proposed uses, estimates of exposure and release, and any health or environmental test data that are available to the submitter. Because there is no explicit statutory authority that requires testing of new chemicals prior to their entry into the market, most PMNs are submitted with little or no data. As a result, EPA has developed special techniques for hazard assessment of PMN chemicals. These include (1) evaluation of available data on the chemical itself, (2) evaluation of data on analogues of the PMN, or evaluation of data on metabolites or analogues of metabolites of the PMN, (3) use of quantitative structure activity relationships (QSARs), and (4) knowledge and judgement of scientific assessors in the interpretation and integration of the information developed in the course of the assessment. This approach to evaluating potential hazards of new chemicals is used to identify those that are most in need of addition review of further testing. It should not be viewed as a replacement for testing. 4 tabs.

  4. Pharmacological activities in thermal proteins: relationships in molecular evolution

    NASA Technical Reports Server (NTRS)

    Fox, S. W.; Hefti, F.; Hartikka, J.; Junard, E.; Przybylski, A. T.; Vaughan, G.

    1987-01-01

    The model of protobiological events that has been presented in these pages has increasing relevance to pharmacological research. The thermal proteins that function as key substances in the proteinoid theory have recently been found to prolong the survival of rat forebrain neurons in culture and to stimulate the growth of neurites. A search for such activity in thermal proteins added to cultures of modern neurons was suggested by the fact that some of the microspheres assembled from proteinoids rich in hydrophobic amino acids themselves generate fibrous outgrowths.

  5. Pharmacological activities in thermal proteins: relationships in molecular evolution.

    PubMed

    Fox, S W; Hefti, F; Hartikka, J; Junard, E; Przybylski, A T; Vaughan, G

    1987-01-01

    The model of protobiological events that has been presented in these pages has increasing relevance to pharmacological research. The thermal proteins that function as key substances in the proteinoid theory have recently been found to prolong the survival of rat forebrain neurons in culture and to stimulate the growth of neurites. A search for such activity in thermal proteins added to cultures of modern neurons was suggested by the fact that some of the microspheres assembled from proteinoids rich in hydrophobic amino acids themselves generate fibrous outgrowths.

  6. Synthesis, biological activity, and quantitative structure-activity relationship study of azanaphthalimide and arylnaphthalimide derivatives.

    PubMed

    Braña, Miguel F; Gradillas, Ana; Gómez, Angel; Acero, Nuria; Llinares, Francisco; Muñoz-Mingarro, Dolores; Abradelo, Cristina; Rey-Stolle, Fernanda; Yuste, Mercedes; Campos, Joaquín; Gallo, Miguel A; Espinosa, Antonio

    2004-04-22

    A series of quinoline derivatives as aza analogues of the naphthalene chromophore and a series of "nonfused" tricyclic aromatic systems, in particular 5-arylquinolines and 5- or 6-aryl and heteroaryl naphthalene systems, were synthesized and evaluated for growth-inhibitory properties in several human cell lines. The analysis of quantitative structure-antitumor activity relationships for the growth-inhibitory properties is also reported. Findings suggest that these compounds may not express their cytotoxicity via interaction on DNA. PMID:15084122

  7. Detecting relationships between physiological variables using graphical models.

    PubMed Central

    Imhoff, Michael; Fried, Ronald; Gather, Ursula

    2002-01-01

    In intensive care physiological variables of the critically ill are measured and recorded in short time intervals. The proper extraction and interpretation of the information contained in this flood of information can hardly be done by experience alone. Intelligent alarm systems are needed to provide suitable bedside decision support. So far there is no commonly accepted standard for detecting the actual clinical state from the patient record. We use the statistical methodology of graphical models based on partial correlations for detecting time-varying relationships between physiological variables. Graphical models provide information on the relationships among physiological variables that is helpful e.g. for variable selection. Separate analyses for different pathophysiological states show that distinct clinical states are characterized by distinct partial correlation structures. Hence, this technique can provide new insights into physiological mechanisms. PMID:12463843

  8. Biophysical properties of Saccharomyces cerevisiae and their relationship with HOG pathway activation.

    PubMed

    Schaber, Jörg; Adrover, Miquel Angel; Eriksson, Emma; Pelet, Serge; Petelenz-Kurdziel, Elzbieta; Klein, Dagmara; Posas, Francesc; Goksör, Mattias; Peter, Mathias; Hohmann, Stefan; Klipp, Edda

    2010-10-01

    Parameterized models of biophysical and mechanical cell properties are important for predictive mathematical modeling of cellular processes. The concepts of turgor, cell wall elasticity, osmotically active volume, and intracellular osmolarity have been investigated for decades, but a consistent rigorous parameterization of these concepts is lacking. Here, we subjected several data sets of minimum volume measurements in yeast obtained after hyper-osmotic shock to a thermodynamic modeling framework. We estimated parameters for several relevant biophysical cell properties and tested alternative hypotheses about these concepts using a model discrimination approach. In accordance with previous reports, we estimated an average initial turgor of 0.6 ± 0.2 MPa and found that turgor becomes negligible at a relative volume of 93.3 ± 6.3% corresponding to an osmotic shock of 0.4 ± 0.2 Osm/l. At high stress levels (4 Osm/l), plasmolysis may occur. We found that the volumetric elastic modulus, a measure of cell wall elasticity, is 14.3 ± 10.4 MPa. Our model discrimination analysis suggests that other thermodynamic quantities affecting the intracellular water potential, for example the matrix potential, can be neglected under physiological conditions. The parameterized turgor models showed that activation of the osmosensing high osmolarity glycerol (HOG) signaling pathway correlates with turgor loss in a 1:1 relationship. This finding suggests that mechanical properties of the membrane trigger HOG pathway activation, which can be represented and quantitatively modeled by turgor. PMID:20563574

  9. Structure-hepatoprotective activity relationship study of sesquiterpene lactones: A QSAR analysis

    NASA Astrophysics Data System (ADS)

    Paukku, Yuliya; Rasulev, Bakhtiyor; Syrov, Vladimir; Khushbaktova, Zainab; Leszczynski, Jerzy

    This study has been carried out using quantitative structure-activity relationship analysis (QSAR) for 22 sesquiterpene lactones to correlate and predict their hepatoprotective activity. Sesquiterpenoids, the largest class of terpenoids, are a widespread group of substances occurring in various plant organisms. QSAR analysis was carried out using methods such as genetic algorithm for variables selection among generated and calculated descriptors and multiple linear regression analysis. Quantum-chemical calculations have been performed by density functional theory at B3LYP/6-311G(d, p) level for evaluation of electronic properties using reference geometries optimized by semi-empirical AM1 approach. Three models describing hepatoprotective activity values for series of sesquiterpene lactones are proposed. The obtained models are useful for description of sesquiterpene lactones hepatoprotective activity and can be used to estimate the hepatoprotective activity of new substituted sesquiterpene lactones. The models obtained in our study show not only statistical significance, but also good predictive ability. The estimated predictive ability (rtest2) of these models lies within 0.942-0.969.

  10. Similitude requirements and scaling relationships as applied to model testing

    NASA Technical Reports Server (NTRS)

    Wolowicz, C. H.; Brown, J. S., Jr.; Gilbert, W. P.

    1979-01-01

    The similitude requirements for the most general test conditions are presented. These similitude requirements are considered in relation to the scaling relationships, test technique, test conditions (including supersonic flow), and test objectives. Particular emphasis is placed on satisfying the various similitude requirements for incompressible and compressible flow conditions. For free flying models tests, the test velocities for incompressible flow are scaled from Froude number similitude requirements and those for compressible flow are scaled from Mach number similitude requirements. The limitations of various test techniques are indicated, with emphasis on the free flying model.

  11. Exploring the structure-activity relationships of ABCC2 modulators using a screening approach.

    PubMed

    Wissel, Gloria; Kudryavtsev, Pavel; Ghemtio, Leo; Tammela, Päivi; Wipf, Peter; Yliperttula, Marjo; Finel, Moshe; Urtti, Arto; Kidron, Heidi; Xhaard, Henri

    2015-07-01

    ABCC2 is a transporter with key influence on liver and kidney pharmacokinetics. In order to explore the structure-activity relationships of compounds that modulate ABCC2, and by doing so gain insights into drug-drug interactions, we screened a library of 432 compounds for modulators of radiolabeled β-estradiol 17-(β-d-glucuronide) (EG) and fluorescent 5(6)-carboxy-2',7'-dichlorofluorescein transport (CDCF) in membrane vesicles. Following the primary screen at 80μM, dose-response curves were used to investigate in detail 86 compounds, identifying 16 low μM inhibitors and providing data about the structure-activity relationships in four series containing 19, 24, 10, and eight analogues. Measurements with the CDCF probe were consistently more robust than for the EG probe. Only one compound was clearly probe-selective with a 50-fold difference in the IC50s obtained by the two assays. We built 24 classification models using the SVM and fused-XY Kohonen methods, revealing molecular descriptors related to number of rings, solubility and lipophilicity as important to distinguish inhibitors from inactive compounds. This study is to the best of our knowledge the first to provide details about structure-activity relationships in ABCC2 modulation. PMID:25935289

  12. Relationship between balance and physical activity measured by an activity monitor in elderly COPD patients

    PubMed Central

    Iwakura, Masahiro; Okura, Kazuki; Shibata, Kazuyuki; Kawagoshi, Atsuyoshi; Sugawara, Keiyu; Takahashi, Hitomi; Shioya, Takanobu

    2016-01-01

    Background Little is known regarding the relationship between balance impairments and physical activity in COPD. There has been no study investigating the relationship between balance and objectively measured physical activity. Here we investigated the association between balance and physical activity measured by an activity monitor in elderly COPD patients. Materials and methods Twenty-two outpatients with COPD (mean age, 72±7 years; forced expiratory volume in 1 second, 53%±21% predicted) and 13 age-matched healthy control subjects (mean age, 72±6 years) participated in the study. We assessed all 35 subjects’ balance (one-leg standing test [OLST] times, Short Physical Performance Battery total scores, standing balance test scores, 4 m gait speed, and five-times sit-to-stand test [5STST]) and physical activity (daily steps and time spent in moderate-to-vigorous physical activity per day [MV-PA]). Possible confounders were assessed in the COPD group. The between-group differences in balance test scores and physical activity were analyzed. A correlation analysis and multivariate regression analysis were conducted in the COPD group. Results The COPD patients exhibited significant reductions in OLST times (P=0.033), Short Physical Performance Battery scores (P=0.013), 4 m gait speed (P<0.001), five-times sit-to-stand times (P=0.002), daily steps (P=0.003), and MV-PA (P=0.022) compared to the controls; the exception was the standing balance test scores. The correlation and multivariate regression analyses revealed significant independent associations between OLST times and daily steps (P<0.001) and between OLST times and MV-PA (P=0.014) in the COPD group after adjusting for possible confounding factors. Conclusion Impairments in balance and reductions in physical activity were observed in the COPD group. Deficits in balance are independently associated with physical inactivity. PMID:27445470

  13. Toxicity of ionic liquids: database and prediction via quantitative structure-activity relationship method.

    PubMed

    Zhao, Yongsheng; Zhao, Jihong; Huang, Ying; Zhou, Qing; Zhang, Xiangping; Zhang, Suojiang

    2014-08-15

    A comprehensive database on toxicity of ionic liquids (ILs) is established. The database includes over 4000 pieces of data. Based on the database, the relationship between IL's structure and its toxicity has been analyzed qualitatively. Furthermore, Quantitative Structure-Activity relationships (QSAR) model is conducted to predict the toxicities (EC50 values) of various ILs toward the Leukemia rat cell line IPC-81. Four parameters selected by the heuristic method (HM) are used to perform the studies of multiple linear regression (MLR) and support vector machine (SVM). The squared correlation coefficient (R(2)) and the root mean square error (RMSE) of training sets by two QSAR models are 0.918 and 0.959, 0.258 and 0.179, respectively. The prediction R(2) and RMSE of QSAR test sets by MLR model are 0.892 and 0.329, by SVM model are 0.958 and 0.234, respectively. The nonlinear model developed by SVM algorithm is much outperformed MLR, which indicates that SVM model is more reliable in the prediction of toxicity of ILs. This study shows that increasing the relative number of O atoms of molecules leads to decrease in the toxicity of ILs.

  14. On the Relationship between Variational Level Set-Based and SOM-Based Active Contours.

    PubMed

    Abdelsamea, Mohammed M; Gnecco, Giorgio; Gaber, Mohamed Medhat; Elyan, Eyad

    2015-01-01

    Most Active Contour Models (ACMs) deal with the image segmentation problem as a functional optimization problem, as they work on dividing an image into several regions by optimizing a suitable functional. Among ACMs, variational level set methods have been used to build an active contour with the aim of modeling arbitrarily complex shapes. Moreover, they can handle also topological changes of the contours. Self-Organizing Maps (SOMs) have attracted the attention of many computer vision scientists, particularly in modeling an active contour based on the idea of utilizing the prototypes (weights) of a SOM to control the evolution of the contour. SOM-based models have been proposed in general with the aim of exploiting the specific ability of SOMs to learn the edge-map information via their topology preservation property and overcoming some drawbacks of other ACMs, such as trapping into local minima of the image energy functional to be minimized in such models. In this survey, we illustrate the main concepts of variational level set-based ACMs, SOM-based ACMs, and their relationship and review in a comprehensive fashion the development of their state-of-the-art models from a machine learning perspective, with a focus on their strengths and weaknesses. PMID:25960736

  15. On the Relationship between Variational Level Set-Based and SOM-Based Active Contours

    PubMed Central

    Abdelsamea, Mohammed M.; Gnecco, Giorgio; Gaber, Mohamed Medhat; Elyan, Eyad

    2015-01-01

    Most Active Contour Models (ACMs) deal with the image segmentation problem as a functional optimization problem, as they work on dividing an image into several regions by optimizing a suitable functional. Among ACMs, variational level set methods have been used to build an active contour with the aim of modeling arbitrarily complex shapes. Moreover, they can handle also topological changes of the contours. Self-Organizing Maps (SOMs) have attracted the attention of many computer vision scientists, particularly in modeling an active contour based on the idea of utilizing the prototypes (weights) of a SOM to control the evolution of the contour. SOM-based models have been proposed in general with the aim of exploiting the specific ability of SOMs to learn the edge-map information via their topology preservation property and overcoming some drawbacks of other ACMs, such as trapping into local minima of the image energy functional to be minimized in such models. In this survey, we illustrate the main concepts of variational level set-based ACMs, SOM-based ACMs, and their relationship and review in a comprehensive fashion the development of their state-of-the-art models from a machine learning perspective, with a focus on their strengths and weaknesses. PMID:25960736

  16. The Structure-Activity Relationship between Marine Algae Polysaccharides and Anti-Complement Activity

    PubMed Central

    Jin, Weihua; Zhang, Wenjing; Liang, Hongze; Zhang, Quanbin

    2015-01-01

    In this study, 33 different polysaccharides were prepared to investigate the structure-activity relationships between the polysaccharides, mainly from marine algae, and anti-complement activity in the classical pathway. Factors considered included extraction methods, fractionations, molecular weight, molar ratio of galactose to fucose, sulfate, uronic acid (UA) content, linkage, branching, and the type of monosaccharide. It was shown that the larger the molecular weights, the better the activities. The molar ratio of galactose (Gal) to fucose (Fuc) was a positive factor at a concentration lower than 10 µg/mL, while it had no effect at a concentration more than 10 µg/mL. In addition, sulfate was necessary; however, the sulfate content, the sulfate pattern, linkage and branching had no effect at a concentration of more than 10 µg/mL. Moreover, the type of monosaccharide had no effect. Laminaran and UA fractions had no activity; however, they could reduce the activity by decreasing the effective concentration of the active composition when they were mixed with the active compositions. The effect of the extraction methods could not be determined. Finally, it was observed that sulfated galactofucan showed good anti-complement activity after separation. PMID:26712768

  17. Modeling species-abundance relationships in multi-species collections

    USGS Publications Warehouse

    Peng, S.; Yin, Z.; Ren, H.; Guo, Q.

    2003-01-01

    Species-abundance relationship is one of the most fundamental aspects of community ecology. Since Motomura first developed the geometric series model to describe the feature of community structure, ecologists have developed many other models to fit the species-abundance data in communities. These models can be classified into empirical and theoretical ones, including (1) statistical models, i.e., negative binomial distribution (and its extension), log-series distribution (and its extension), geometric distribution, lognormal distribution, Poisson-lognormal distribution, (2) niche models, i.e., geometric series, broken stick, overlapping niche, particulate niche, random assortment, dominance pre-emption, dominance decay, random fraction, weighted random fraction, composite niche, Zipf or Zipf-Mandelbrot model, and (3) dynamic models describing community dynamics and restrictive function of environment on community. These models have different characteristics and fit species-abundance data in various communities or collections. Among them, log-series distribution, lognormal distribution, geometric series, and broken stick model have been most widely used.

  18. Structure-activity relationship for Fe(III)-salen-like complexes as potent anticancer agents.

    PubMed

    Ghanbari, Zahra; Housaindokht, Mohammad R; Izadyar, Mohammad; Bozorgmehr, Mohammad R; Eshtiagh-Hosseini, Hossein; Bahrami, Ahmad R; Matin, Maryam M; Khoshkholgh, Maliheh Javan

    2014-01-01

    Quantitative structure activity relationship (QSAR) for the anticancer activity of Fe(III)-salen and salen-like complexes was studied. The methods of density function theory (B3LYP/LANL2DZ) were used to optimize the structures. A pool of descriptors was calculated: 1497 theoretical descriptors and quantum-chemical parameters, shielding NMR, and electronic descriptors. The study of structure and activity relationship was performed with multiple linear regression (MLR) and artificial neural network (ANN). In nonlinear method, the adaptive neuro-fuzzy inference system (ANFIS) was applied in order to choose the most effective descriptors. The ANN-ANFIS model with high statistical significance (R (2) train = 0.99, RMSE = 0.138, and Q (2) LOO = 0.82) has better capability to predict the anticancer activity of the new compounds series of this family. Based on this study, anticancer activity of this compound is mainly dependent on the geometrical parameters, position, and the nature of the substituent of salen ligand. PMID:24955417

  19. Structure-Activity Relationship for Fe(III)-Salen-Like Complexes as Potent Anticancer Agents

    PubMed Central

    Ghanbari, Zahra; Housaindokht, Mohammad R.; Izadyar, Mohammad; Bozorgmehr, Mohammad R.; Eshtiagh-Hosseini, Hossein; Bahrami, Ahmad R.; Matin, Maryam M.; Khoshkholgh, Maliheh Javan

    2014-01-01

    Quantitative structure activity relationship (QSAR) for the anticancer activity of Fe(III)-salen and salen-like complexes was studied. The methods of density function theory (B3LYP/LANL2DZ) were used to optimize the structures. A pool of descriptors was calculated: 1497 theoretical descriptors and quantum-chemical parameters, shielding NMR, and electronic descriptors. The study of structure and activity relationship was performed with multiple linear regression (MLR) and artificial neural network (ANN). In nonlinear method, the adaptive neuro-fuzzy inference system (ANFIS) was applied in order to choose the most effective descriptors. The ANN-ANFIS model with high statistical significance (R2train = 0.99, RMSE = 0.138, and Q2LOO = 0.82) has better capability to predict the anticancer activity of the new compounds series of this family. Based on this study, anticancer activity of this compound is mainly dependent on the geometrical parameters, position, and the nature of the substituent of salen ligand. PMID:24955417

  20. An investigation into the relationship between age and physiological function in highly active older adults

    PubMed Central

    Pollock, Ross D; Carter, Scott; Velloso, Cristiana P; Duggal, Niharika A; Lord, Janet M; Lazarus, Norman R; Harridge, Stephen D R

    2015-01-01

    Despite extensive research, the relationship between age and physiological function remains poorly characterised and there are currently no reliable markers of human ageing. This is probably due to a number of confounding factors, particularly in studies of a cross-sectional nature. These include inter-subject genetic variation, as well as inter-generational differences in nutrition, healthcare and insufficient levels of physical activity as well as other environmental factors. We have studied a cohort of highly and homogeneously active older male (n = 84) and female (n = 41) cyclists aged 55–79 years who it is proposed represent a model for the study of human ageing free from the majority of confounding factors, especially inactivity. The aim of the study was to identify physiological markers of ageing by assessing the relationship between function and age across a wide range of indices. Each participant underwent a detailed physiological profiling which included measures of cardiovascular, respiratory, neuromuscular, metabolic, endocrine and cognitive functions, bone strength, and health and well-being. Significant associations between age and function were observed for many functions. The maximal rate of oxygen consumption ( showed the closest association with age (r = −0.443 to −0.664; P < 0.001), but even here the variance in age for any given level was high, precluding the clear identification of the age of any individual. The results of this cross-sectional study suggest that even when many confounding variables are removed the relationship between function and healthy ageing is complex and likely to be highly individualistic and that physical activity levels must be taken into account in ageing studies. Key Points The relationship between age and physiological function remains poorly defined and there are no physiological markers that can be used to reliably predict the age of an individual. This could be due to a variety of confounding

  1. American Time Use Survey: Sleep Time and Its Relationship to Waking Activities

    PubMed Central

    Basner, Mathias; Fomberstein, Kenneth M.; Razavi, Farid M.; Banks, Siobhan; William, Jeffrey H.; Rosa, Roger R.; Dinges, David F.

    2007-01-01

    Study Objectives: To gain some insight into how various behavioral (lifestyle) factors influence sleep duration, by investigation of the relationship of sleep time to waking activities using the American Time Use Survey (ATUS). Design: Cross-sectional data from ATUS, an annual telephone survey of a population sample of US citizens who are interviewed regarding how they spent their time during a 24-hour period between 04:00 on the previous day and 04:00 on the interview day. Participants: Data were pooled from the 2003, 2004, and 2005 ATUS databases involving N=47,731 respondents older than 14 years of age. Interventions: N/A Results: Adjusted multiple linear regression models showed that the largest reciprocal relationship to sleep was found for work time, followed by travel time, which included commute time. Only shorter than average sleepers (<7.5 h) spent more time socializing, relaxing, and engaging in leisure activities, while both short (<5.5 h) and long sleepers (≥8.5 h) watched more TV than the average sleeper. The extent to which sleep time was exchanged for waking activities was also shown to depend on age and gender. Sleep time was minimal while work time was maximal in the age group 45–54 yr, and sleep time increased both with lower and higher age. Conclusions: Work time, travel time, and time for socializing, relaxing, and leisure are the primary activities reciprocally related to sleep time among Americans. These activities may be confounding the frequently observed association between short and long sleep on one hand and morbidity and mortality on the other hand and should be controlled for in future studies. Citation: Basner M; Fomberstein KM; Razavi FM; Banks S; William JH; Rosa RR; Dinges DF. American time use survey: sleep time and its relationship to waking activities. SLEEP 2007;30(9):1085-1095. PMID:17910380

  2. Quantitative structure-activity relationships of selective antagonists of glucagon receptor using QuaSAR descriptors.

    PubMed

    Manoj Kumar, Palanivelu; Karthikeyan, Chandrabose; Hari Narayana Moorthy, Narayana Subbiah; Trivedi, Piyush

    2006-11-01

    In the present paper, quantitative structure activity relationship (QSAR) approach was applied to understand the affinity and selectivity of a novel series of triaryl imidazole derivatives towards glucagon receptor. Statistically significant and highly predictive QSARs were derived for glucagon receptor inhibition by triaryl imidazoles using QuaSAR descriptors of molecular operating environment (MOE) employing computer-assisted multiple regression procedure. The generated QSAR models revealed that factors related to hydrophobicity, molecular shape and geometry predominantly influences glucagon receptor binding affinity of the triaryl imidazoles indicating the relevance of shape specific steric interactions between the molecule and the receptor. Further, QSAR models formulated for selective inhibition of glucagon receptor over p38 mitogen activated protein (MAP) kinase of the compounds in the series highlights that the same structural features, which influence the glucagon receptor affinity, also contribute to their selective inhibition.

  3. 24 CFR 1006.225 - Model activities.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... 24 Housing and Urban Development 4 2012-04-01 2012-04-01 false Model activities. 1006.225 Section... NATIVE HAWAIIAN HOUSING BLOCK GRANT PROGRAM Eligible Activities § 1006.225 Model activities. NHHBG funds may be used for housing activities under model programs that are: (a) Designed to carry out...

  4. 24 CFR 1006.225 - Model activities.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... 24 Housing and Urban Development 4 2013-04-01 2013-04-01 false Model activities. 1006.225 Section... NATIVE HAWAIIAN HOUSING BLOCK GRANT PROGRAM Eligible Activities § 1006.225 Model activities. NHHBG funds may be used for housing activities under model programs that are: (a) Designed to carry out...

  5. 24 CFR 1006.225 - Model activities.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 24 Housing and Urban Development 4 2011-04-01 2011-04-01 false Model activities. 1006.225 Section... NATIVE HAWAIIAN HOUSING BLOCK GRANT PROGRAM Eligible Activities § 1006.225 Model activities. NHHBG funds may be used for housing activities under model programs that are: (a) Designed to carry out...

  6. 24 CFR 1006.225 - Model activities.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... 24 Housing and Urban Development 4 2014-04-01 2014-04-01 false Model activities. 1006.225 Section... NATIVE HAWAIIAN HOUSING BLOCK GRANT PROGRAM Eligible Activities § 1006.225 Model activities. NHHBG funds may be used for housing activities under model programs that are: (a) Designed to carry out...

  7. In vitro-in vivo activity relationship of substituted benzimidazole cell division inhibitors with activity against Mycobacteria tuberculosis

    PubMed Central

    Knudson, Susan E.; Kumar, Kunal; Awasthi, Divya; Ojima, Iwao; Slayden, Richard A.

    2014-01-01

    Structure based drug design was used to develop a compound library of novel 2,5,6- and 2,5,7-trisubstituted benzimidazoles. Three structural analogs, SB-P1G10, SB-P8B2 and SB-P3G2 were selected from this library based on previous studies for advanced study. In vitro studies revealed that SB-P8B2 and SB-P3G2 had sigmoidal kill-curves while in contrast SB-P1G10 showed a narrow zonal susceptibility. The in vitro studies also demonstrated that exposure to SB-P8B2 or SB-P3G2 was bactericidal, while SB-P1G10 treatment never resulted in complete killing. The dose curves for the three compounds against clinical isolates were comparable to their respective dose curves in the laboratory strain of M. tuberculosis. SB-P8B2 and SB-P3G2 exhibited antibacterial activity against non-replicating bacilli under low oxygen conditions. SB-P3G2 and SB-P1G10 were assessed in acute short-term animal models of tuberculosis, which showed that SB-P3G2 treatment demonstrated activity against M. tuberculosis. Together, these studies reveal an in vitro- in vivo relationship of the 2,5,6-trisubstituted benzimidazoles that serves as a criterion for advancing this class of cell division inhibitors into more resource intensive in vivo efficacy models such as the long-term murine model of tuberculosis and Pre-IND PK/PD studies. Specifically, these studies are the first demonstration of efficacy and an in vitro–in vivo activity relationship for 2,5,6-trisubstituted benzimidazoles. The in vivo activity presented in this manuscript substantiates this class of cell division inhibitors as having potency and efficacy against M. tuberculosis. PMID:24746463

  8. Does community type moderate the relationship between parent perceptions of the neighborhood and physical activity in children?

    PubMed Central

    Dunton, Genevieve F.; Spruijt-Metz, Donna; Pentz, Mary Ann

    2014-01-01

    Purpose To examine whether residing in a community designed to promote physical activity moderates the relationship between parent perceptions of the neighborhood and general physical activity or active commuting to school in their children. Design Cross-sectional Setting San Bernardino County, California. Subjects 365 families (one parent and one child in grades 4th-8th). 85 reside in a smart growth community designed to be more conducive to physical activity. Measures Parent perceptions assessed using the Neighborhood Environment Walkability Scale. General child physical activity measured using accelerometers, and active commuting was self-reported by children. Analysis Two sets of regressions were performed: one for general physical activity, and one for active commuting. Separate models were run in the two sets for each of the 14 NEWS factors, while controlling for demographics. Results For general physical activity, walking infrastructure, lack of cul-de-sacs and social interaction had significant main effect associations (p≤0.05). No factors were moderated by community. The relationships between active commuting to school and perceived crime, traffic hazards, hilliness, physical barriers, cul-de-sac connectivity, aesthetics, and walking infrastructure were significant for those in the smart growth community only (p≤0.05). Conclusions Living in an activity friendly environment is associated with positive relationships between parent perceptions and active commuting behaviors in children. Future interventions should account for both the perceived neighborhood environment and available physical activity infrastructure. PMID:22747320

  9. A Combined Quantitative Structure-Activity Relationship Research of Quinolinone Derivatives as Androgen Receptor Antagonists.

    PubMed

    Wang, Yuwei; Bai, Fang; Cao, Hong; Li, Jiazhong; Liu, Huanxiang; Gramatica, Paola

    2015-01-01

    Antiandrogens bicalutamide, flutamide and enzalutamide etc. have been used in clinical trials to treat prostate cancer by binding to and antagonizing androgen receptor (AR). Although initially effective, the drug resistance problem will emerge eventually, which results in a high medical need for novel AR antagonist exploitation. Here in this work, to facilitate the rational design of novel AR antagonists, we studied the structure-activity relationships of a series of 2-quinolinone derivatives and investigated the structural requirements for their antiandrogenic activities. Different modeling methods, including 2D MLR, 3D CoMFA and CoMSIA, were implemented to evolve QSAR models. All these models, thoroughly validated, demonstrated satisfactory results especially for the good predictive abilities. The contour maps from 3D CoMFA and CoMSIA models provide visualized explanation of key structural characteristics relevant to the antiandrogenic activities, which is summarized to a position-specific conclusion at the end. The obtained results from this research are practically useful for rational design and screening of promising chemicals with high antiandrogenic activities.

  10. Identification of New Nonsteroidal RORα Ligands; Related Structure–Activity Relationships and Docking Studies

    PubMed Central

    2013-01-01

    A high throughput screen was developed to identify novel, nonsteroidal RORα agonists. Among the validated hit compounds, the 4-(4-(benzyloxy)phenyl)-5-carbonyl-2-oxo-1,2,3,4-tetrahydropyrimidine scaffold was the most prominent. Among the numerous analogues tested, compounds 8 and 9 showed the highest activity. Key structure–activity relationships (SAR) were established, where benzyl and urea moieties were both identified as very important elements to maintain the activity. Most notably, the SAR were consistent with the binding mode of the compound 8 (S-isomer) in the RORα docking model that was developed in this program. As predicted by the model, the urea moiety is engaged in the formation of key hydrogen bonds with the backbone of Tyr380 and Asp382. The benzyl group is located in a wide hydrophobic pocket. The structural relationships reported in this letter will help in further optimization of this compound series and will provide novel synthetic probes helpful for elucidation of complex RORα physiopathology. PMID:24900700

  11. Identification of New Nonsteroidal RORα Ligands; Related Structure-Activity Relationships and Docking Studies.

    PubMed

    Dubernet, Mathieu; Duguet, Nicolas; Colliandre, Lionel; Berini, Christophe; Helleboid, Stéphane; Bourotte, Marilyne; Daillet, Matthieu; Maingot, Lucie; Daix, Sébastien; Delhomel, Jean-François; Morin-Allory, Luc; Routier, Sylvain; Walczak, Robert

    2013-06-13

    A high throughput screen was developed to identify novel, nonsteroidal RORα agonists. Among the validated hit compounds, the 4-(4-(benzyloxy)phenyl)-5-carbonyl-2-oxo-1,2,3,4-tetrahydropyrimidine scaffold was the most prominent. Among the numerous analogues tested, compounds 8 and 9 showed the highest activity. Key structure-activity relationships (SAR) were established, where benzyl and urea moieties were both identified as very important elements to maintain the activity. Most notably, the SAR were consistent with the binding mode of the compound 8 (S-isomer) in the RORα docking model that was developed in this program. As predicted by the model, the urea moiety is engaged in the formation of key hydrogen bonds with the backbone of Tyr380 and Asp382. The benzyl group is located in a wide hydrophobic pocket. The structural relationships reported in this letter will help in further optimization of this compound series and will provide novel synthetic probes helpful for elucidation of complex RORα physiopathology.

  12. KNApSAcK Metabolite Activity Database for retrieving the relationships between metabolites and biological activities.

    PubMed

    Nakamura, Yukiko; Afendi, Farit Mochamad; Parvin, Aziza Kawsar; Ono, Naoaki; Tanaka, Ken; Hirai Morita, Aki; Sato, Tetsuo; Sugiura, Tadao; Altaf-Ul-Amin, Md; Kanaya, Shigehiko

    2014-01-01

    Databases (DBs) are required by various omics fields because the volume of molecular biology data is increasing rapidly. In this study, we provide instructions for users and describe the current status of our metabolite activity DB. To facilitate a comprehensive understanding of the interactions between the metabolites of organisms and the chemical-level contribution of metabolites to human health, we constructed a metabolite activity DB known as the KNApSAcK Metabolite Activity DB. It comprises 9,584 triplet relationships (metabolite-biological activity-target species), including 2,356 metabolites, 140 activity categories, 2,963 specific descriptions of biological activities and 778 target species. Approximately 46% of the activities described in the DB are related to chemical ecology, most of which are attributed to antimicrobial agents and plant growth regulators. The majority of the metabolites with antimicrobial activities are flavonoids and phenylpropanoids. The metabolites with plant growth regulatory effects include plant hormones. Over half of the DB contents are related to human health care and medicine. The five largest groups are toxins, anticancer agents, nervous system agents, cardiovascular agents and non-therapeutic agents, such as flavors and fragrances. The KNApSAcK Metabolite Activity DB is integrated within the KNApSAcK Family DBs to facilitate further systematized research in various omics fields, especially metabolomics, nutrigenomics and foodomics. The KNApSAcK Metabolite Activity DB could also be utilized for developing novel drugs and materials, as well as for identifying viable drug resources and other useful compounds.

  13. Structural equation models of relationships between exercise and cognitive abilities.

    PubMed

    Clarkson-Smith, L; Hartley, A A

    1990-09-01

    Data were obtained from 300 men and women aged 55 to 91. Separate structural equation models of relationships between physical exercise and 3 cognitive performance variables--reaction time, working memory, and reasoning--fit the data well. Other variables in the models were age, health, education, and morale. Age and exercise affected each performance variable directly; education had a direct effect on reasoning only. There were also indirect effects of age and health on performance variables, mediated through exercise. The main hypothesis of the study, that exercise contributes to performance, was supported. A large decrease in model fit resulted when the path from exercise to each performance variable was deleted. Hypotheses that age-related deficits are primarily accounted for by lack of exercise or by poor health were not supported.

  14. Modeling relationships between calving traits: a comparison between standard and recursive mixed models

    PubMed Central

    2010-01-01

    Background The use of structural equation models for the analysis of recursive and simultaneous relationships between phenotypes has become more popular recently. The aim of this paper is to illustrate how these models can be applied in animal breeding to achieve parameterizations of different levels of complexity and, more specifically, to model phenotypic recursion between three calving traits: gestation length (GL), calving difficulty (CD) and stillbirth (SB). All recursive models considered here postulate heterogeneous recursive relationships between GL and liabilities to CD and SB, and between liability to CD and liability to SB, depending on categories of GL phenotype. Methods Four models were compared in terms of goodness of fit and predictive ability: 1) standard mixed model (SMM), a model with unstructured (co)variance matrices; 2) recursive mixed model 1 (RMM1), assuming that residual correlations are due to the recursive relationships between phenotypes; 3) RMM2, assuming that correlations between residuals and contemporary groups are due to recursive relationships between phenotypes; and 4) RMM3, postulating that the correlations between genetic effects, contemporary groups and residuals are due to recursive relationships between phenotypes. Results For all the RMM considered, the estimates of the structural coefficients were similar. Results revealed a nonlinear relationship between GL and the liabilities both to CD and to SB, and a linear relationship between the liabilities to CD and SB. Differences in terms of goodness of fit and predictive ability of the models considered were negligible, suggesting that RMM3 is plausible. Conclusions The applications examined in this study suggest the plausibility of a nonlinear recursive effect from GL onto CD and SB. Also, the fact that the most restrictive model RMM3, which assumes that the only cause of correlation is phenotypic recursion, performs as well as the others indicates that the phenotypic recursion

  15. 30-year Dynamics of Terrestrial Vegetation Activity and the Relationship with Climatologies

    NASA Astrophysics Data System (ADS)

    de Jong, R.; Schaepman, M. E.; Furrer, R.; de Bruin, S.; Verburg, P. H.

    2013-12-01

    The climate governs the seasonal activity of terrestrial vegetation while humankind influences it. The relative role of these drivers in changing vegetation activity is crucial information for accurate modeling of vegetation and climate dynamics and for adaptation and mitigation strategies. Disentangling the two, however, is an ongoing scientific challenge, because of limited data availability, mainly regarding non-climatic drivers, and complex biosphere-atmosphere feedback mechanisms. Here, we contribute to this quest by modeling the spatial relationship between climatologies and changes in global vegetation activity (de Jong et al., 2013a). Vegetation activity is commonly quantified using remotely sensed vegetation indices (VI). Extensive reports on temporal trends over the past decades in time series of such indices can be found in literature, including the detection of shifts (de Jong et al., 2013b), which may be related to climate (e.g. Zhao & Running, 2010). However, little remains known about the exact processes underlying vegetation change at large spatial scales. Depending on eco-region, three climatologies potentially constrain plant growth (Churkina and Running, 1998). In the humid mid-latitudes, for example, temperature is the largest influencing factor; in (semi) arid regions it is the availability of water and in the tropics incident solar radiation. Based on this logic, we developed a mixed-effect model to relate changes in these climatologies to changes in vegetation activity and to quantify the spatial process underlying the other drivers, including human land use. Little over 50% of the spatial variation in vegetation change could be attributed to changes in climatologies; conspicuously, many of the global ';greening' trends and the ';browning' hotspots in Argentina and Australia. Browning hotspots in the non-climatic component were especially located in subequatorial Africa (e.g. parts of Zimbabwe and Tanzania), where human drivers may be

  16. HydroCube: an entity-relationship hydrogeological data model

    NASA Astrophysics Data System (ADS)

    Wojda, Piotr; Brouyère, Serge; Derouane, Johan; Dassargues, Alain

    2010-12-01

    Managing, handling and accessing hydrogeological information depends heavily on the applied hydrogeological data models, which differ between institutions and countries. The effective dissemination of hydrogeological information requires the convergence of such models to make hydrogeological information accessible to multiple users such as universities, water suppliers, and administration and research organisations. Furthermore, because hydrogeological studies are complex, they require a wide variety of high-quality hydrogeological data with appropriate metadata in clearly designed and coherent structures. A need exists, therefore, to develop and implement hydrogeological data models that cover, as much as possible, the full hydrogeological domain. A new data model, called HydroCube, was developed for the Walloon Region in Belgium in 2005. The HydroCube model presents an innovative holistic project-based approach which covers a full set of hydrogeological concepts and features, allowing for effective hydrogeological project management. The model stores data relating to the project locality, hydrogeological equipment, and related observations and measurements. In particular, it focuses on specialized hydrogeological field experiments such as pumping and tracer tests. This logical data model uses entity-relationship diagrams and it has been implemented in the Microsoft Access environment. It has been enriched with a fully functional user interface.

  17. Modelling the maximum voluntary joint torque/angular velocity relationship in human movement.

    PubMed

    Yeadon, Maurice R; King, Mark A; Wilson, Cassie

    2006-01-01

    The force exerted by a muscle is a function of the activation level and the maximum (tetanic) muscle force. In "maximum" voluntary knee extensions muscle activation is lower for eccentric muscle velocities than for concentric velocities. The aim of this study was to model this "differential activation" in order to calculate the maximum voluntary knee extensor torque as a function of knee angular velocity. Torque data were collected on two subjects during maximal eccentric-concentric knee extensions using an isovelocity dynamometer with crank angular velocities ranging from 50 to 450 degrees s(-1). The theoretical tetanic torque/angular velocity relationship was modelled using a four parameter function comprising two rectangular hyperbolas while the activation/angular velocity relationship was modelled using a three parameter function that rose from submaximal activation for eccentric velocities to full activation for high concentric velocities. The product of these two functions gave a seven parameter function which was fitted to the joint torque/angular velocity data, giving unbiased root mean square differences of 1.9% and 3.3% of the maximum torques achieved. Differential activation accounts for the non-hyperbolic behaviour of the torque/angular velocity data for low concentric velocities. The maximum voluntary knee extensor torque that can be exerted may be modelled accurately as the product of functions defining the maximum torque and the maximum voluntary activation level. Failure to include differential activation considerations when modelling maximal movements will lead to errors in the estimation of joint torque in the eccentric phase and low velocity concentric phase.

  18. Quantitative structure-activity relationship for toxicity of ionic liquids to Daphnia magna: aromaticity vs. lipophilicity.

    PubMed

    Roy, Kunal; Das, Rudra Narayan; Popelier, Paul L A

    2014-10-01

    Water solubility of ionic liquids (ILs) allows their dispersion into aquatic systems and raises concerns on their pollutant potential. Again, lipophilicity can contribute to the toxicity of ILs due to increased ability of the compounds to cross lipoidal bio-membranes. In the present work, we have performed statistical model development for toxicity of a set of ionic liquids to Daphnia magna, a widely accepted model organism for toxicity testing, using computed lipophilicity, atom-type fragment, quantum topological molecular similarity (QTMS) and extended topochemical atom (ETA) descriptors. The models have been developed and validated in accordance with the Organization for Economic Co-operation and Development (OECD) guidelines for quantitative structure-activity relationships (QSARs). The best partial least squares (PLS) model outperforms the previously reported multiple linear regression (MLR) model in statistical quality and predictive ability (R(2)=0.955, Q(2)=0.917, Rpred(2)=0.848). In this work, the ETA descriptors show importance of branching and aromaticity while the QTMS descriptor ellipticity efficiently shows which compounds are influential in the data set, with reference to the model. While obvious importance of lipophilicity is evident from the models, the best model clearly shows the importance of aromaticity suggesting that more lipophilic ILs with less toxicity may be designed by avoiding aromaticity, nitrogen atoms and increasing branching in the cationic structure. The developed quantitative models are in consonance with the recent hypothesis of importance of aromaticity for toxicity of ILs.

  19. Synthesis, insecticidal activity, and structure-activity relationship (SAR) of anthranilic diamides analogs containing oxadiazole rings.

    PubMed

    Li, Yuhao; Zhu, Hongjun; Chen, Kai; Liu, Rui; Khallaf, Abdalla; Zhang, Xiangning; Ni, Jueping

    2013-06-28

    A series of anthranilic diamides analogs (3–11, 16–24) containing 1,2,4- or 1,3,4-oxadiazole rings were synthesized and characterized by (1)H NMR, MS and elemental analyses. The structure of 3-bromo-N-(2-(3-(4-bromophenyl)-1,2,4-oxadiazol-5-yl)-4-chloro-6-methylphenyl)-1-(3-chloropyridin-2-yl)-1H-pyrazole-5-carboxamide (18, CCDC-) was determined by X-ray diffraction crystallography. The insecticidal activities against Plutella xylostella and Spodoptera exigua were evaluated. The results showed that most of title compounds displayed good larvicidal activities against P. xylostella, especially compound 3-bromo-N-(4-chloro-2-methyl-6-(5-(methylthio)-1,3,4-oxadiazol-2-yl)phenyl)-1-(3-chloropyridin-2-yl)-1H-pyrazole-5-carboxamide (6), which displayed 71.43% activity against P. xylostella at 0.4 μg mL(-1) and 33.33% against S. exigua at 1 μg mL(-1). The structure-activity relationship showed that compounds decorated with a 1,3,4-oxadiazole were more potent than compounds decorated with a 1,2,4-oxadiazole, and different substituents attached to the oxadiazole ring also affected the insecticidal activity. This work provides some hints for further structure modification and the enhancement of insecticidal activity.

  20. Structure-activity relationships for antioxidant activities of a series of flavonoids in a liposomal system.

    PubMed

    Arora, A; Nair, M G; Strasburg, G M

    1998-06-01

    Structurally diverse plant phenolics were examined for their abilities to inhibit lipid peroxidation induced either by Fe(II) and Fe(III) metal ions or by azo-derived peroxyl radicals in a liposomal membrane system. The antioxidant abilities of flavonoids were compared with those of coumarin and tert-butylhydroquinone (TBHQ). The antioxidant efficacies of these compounds were evaluated on the basis of their abilities to inhibit the fluorescence intensity decay of an extrinsic probe, 3-(p-(6-phenyl)-I,3,5-hexatrienyl)phenylpropionic acid (DPH-PA), caused by the free radicals generated during lipid peroxidation. All the flavonoids tested exhibited higher antioxidant efficacies against metal-ion-induced peroxidations than peroxyl-radical-induced peroxidation, suggesting that metal chelation may play a larger role in determining the antioxidant activities of these compounds than has previously been believed. Distinct structure-activity relationships were also revealed for the antioxidant abilities of the flavonoids. Presence of hydroxyl substituents on the flavonoid nucleus enhanced activity, whereas substitution by methoxy groups diminished antioxidant activity. Substitution patterns on the B-ring especially affected antioxidant potencies of the flavonoids. In cases where the B-ring could not contribute to the antioxidant activities of flavonoids, hydroxyl substituents in an catechol structure on the A-ring were able to compensate and become a larger determinant of flavonoid antioxidant activity. PMID:9641252

  1. Synthesis, insecticidal activity, and structure-activity relationship (SAR) of anthranilic diamides analogs containing oxadiazole rings.

    PubMed

    Li, Yuhao; Zhu, Hongjun; Chen, Kai; Liu, Rui; Khallaf, Abdalla; Zhang, Xiangning; Ni, Jueping

    2013-06-28

    A series of anthranilic diamides analogs (3–11, 16–24) containing 1,2,4- or 1,3,4-oxadiazole rings were synthesized and characterized by (1)H NMR, MS and elemental analyses. The structure of 3-bromo-N-(2-(3-(4-bromophenyl)-1,2,4-oxadiazol-5-yl)-4-chloro-6-methylphenyl)-1-(3-chloropyridin-2-yl)-1H-pyrazole-5-carboxamide (18, CCDC-) was determined by X-ray diffraction crystallography. The insecticidal activities against Plutella xylostella and Spodoptera exigua were evaluated. The results showed that most of title compounds displayed good larvicidal activities against P. xylostella, especially compound 3-bromo-N-(4-chloro-2-methyl-6-(5-(methylthio)-1,3,4-oxadiazol-2-yl)phenyl)-1-(3-chloropyridin-2-yl)-1H-pyrazole-5-carboxamide (6), which displayed 71.43% activity against P. xylostella at 0.4 μg mL(-1) and 33.33% against S. exigua at 1 μg mL(-1). The structure-activity relationship showed that compounds decorated with a 1,3,4-oxadiazole were more potent than compounds decorated with a 1,2,4-oxadiazole, and different substituents attached to the oxadiazole ring also affected the insecticidal activity. This work provides some hints for further structure modification and the enhancement of insecticidal activity. PMID:23657615

  2. Using Bayesian Networks to Model Hierarchical Relationships in Epidemiological Studies

    PubMed Central

    2011-01-01

    OBJECTIVES To propose an alternative procedure, based on a Bayesian network (BN), for estimation and prediction, and to discuss its usefulness for taking into account the hierarchical relationships among covariates. METHODS The procedure is illustrated by modeling the risk of diarrhea infection for 2,740 children aged 0 to 59 months in Cameroon. We compare the procedure with a standard logistic regression and with a model based on multi-level logistic regression. RESULTS The standard logistic regression approach is inadequate, or at least incomplete, in that it does not attempt to account for potentially causal relationships between risk factors. The multi-level logistic regression does model the hierarchical structure, but does so in a piecewise manner; the resulting estimates and interpretations differ from those of the BN approach proposed here. An advantage of the BN approach is that it enables one to determine the probability that a risk factor (and/or the outcome) is in any specific state, given the states of the others. The currently available approaches can only predict the outcome (disease), given the states of the covariates. CONCLUSION A major advantage of BNs is that they can deal with more complex interrelationships between variables whereas competing approaches deal at best only with hierarchical ones. We propose that BN be considered as well as a worthwhile method for summarizing the data in epidemiological studies whose aim is understanding the determinants of diseases and quantifying their effects. PMID:21779534

  3. Considering complementary relationship of evaporation in Budyko's hydrological model

    NASA Astrophysics Data System (ADS)

    Han, Songjun; Shao, Weiwei

    2013-04-01

    In Budyko's hydrological model, actual evaporation was partitioned from precipitation as a function of the relative magnitude of precipitation and potential evaporation. In practice, both Penman equation and Priestley-Taylor equation have been used to estimate the potential evaporation with same Budyko curve, and they are not distinguished under Budyko framework. Nevertheless, according to the complementary relationship of evaporation, the definitions of Penman equation and Priestley-Taylor equation are absolutely different. When water availability is not limited, evaporation occurs at Priestley-Taylor's evaporation (Ew, referred to as wet environment evaporation). As the surface dries without changing the available energy, the actual and Penman's potential evaporation (Epen) rates depart from Ew with opposite changes in fluxes. So the question is: what is the difference of the Budyko's hydrological model with potential evaporation estimated by Penman or Priestley-Taylor equation? How to consider the complementary relationship in Budyko framework? In this study, for both long-term (multiyear) and annual values on water balances in the 29 non-humid catchments in the middle Yellow River Basin of China, the performances of Budyko's hydrological model with potential evaporation estimated by Epen and Ew were distinguished and compared. The catchments with larger value of Ep/Ew (ratio of Penman potential evaporation to Priestley-Taylor evaporation) are characterized with smaller evaporation ratios. The value of Ep/Ew can be served as another variable besides dryness index to partition actual evaporation from precipitation. With Priestley-Taylor equation as energy supply, an empirical formula for the parameter of the Budyko in terms of Ep/Ew and curve is proposed. Therefore, the complementary relationship of evaporation should be considered in the Budyko framework.

  4. Quantitative structure-activity/ecotoxicity relationships (QSAR/QEcoSAR) of a series of phosphonates.

    PubMed

    Petrescu, Alina-Maria; Putz, Mihai V; Ilia, Gheorghe

    2015-11-01

    In this paper the structure-toxicity relationship studies were performed for a series of 60 phosphonates. The toxicity of the compounds was determined by two ways: by quantifying the measured toxicity values, Mlog(1/MRIC50) collected by literature, for rodents species; second by using EcoSAR software version 1.11, for calculating the toxicity for fish species, considered as dependent variables and they were related to structural features obtained by molecular and quantum mechanics calculations. The QSAR/QEcoSAR was validated by multiple linear regression (MLR), although the purpose of this work was not to validate the model proposed, but rather to test the influence of structural parameters of the proposed model QSAR/QEcoSAR. The obtained models showed that the toxicity of phosphonates was influenced by steric and molecular geometry which cause inhibition of cholinesterase activity.

  5. Software Engineering Laboratory (SEL) relationships, models, and management rules

    NASA Technical Reports Server (NTRS)

    Decker, William; Hendrick, Robert; Valett, Jon D.

    1991-01-01

    Over 50 individual Software Engineering Laboratory (SEL) research results, extracted from a review of published SEL documentation, that can be applied directly to managing software development projects are captured. Four basic categories of results are defined and discussed - environment profiles, relationships, models, and management rules. In each category, research results are presented as a single page that summarizes the individual result, lists potential uses of the result by managers, and references the original SEL documentation where the result was found. The document serves as a concise reference summary of applicable research for SEL managers.

  6. China's Marriage Law: a model for family responsibilities and relationships.

    PubMed

    Hare-Mustin, R T

    1982-12-01

    China's Marriage Law of 1981 is presented with a brief commentary. The law encompasses the responsibilities of spouses, parents, children, grandparents, and siblings to one another. The new law is contrasted with the 1950 Marriage Law, which prohibited such feudal practices of former times as arranged marriages and child betrothals. The 1981 law is concerned with equality and the lawful needs of women, children, and the aged. Family planning is encouraged. Divorce is made easier to obtain. Adoptees and stepchildren are provided for. The law provides a legislative model for personal relationships.

  7. China's Marriage Law: a model for family responsibilities and relationships.

    PubMed

    Hare-Mustin, R T

    1982-12-01

    China's Marriage Law of 1981 is presented with a brief commentary. The law encompasses the responsibilities of spouses, parents, children, grandparents, and siblings to one another. The new law is contrasted with the 1950 Marriage Law, which prohibited such feudal practices of former times as arranged marriages and child betrothals. The 1981 law is concerned with equality and the lawful needs of women, children, and the aged. Family planning is encouraged. Divorce is made easier to obtain. Adoptees and stepchildren are provided for. The law provides a legislative model for personal relationships. PMID:7160464

  8. A test of an expert-based bird-habitat relationship model in South Carolina.

    SciTech Connect

    Kilgo, John, C.; Gartner, David, L.; Chapman, Brian, R.; Dunning, John, B., Jr.; Franzreb, Kathleen, E.; Gauthreaux, Sidney, A.; Greenberg, Catheryn, H.; Levey, Douglas, J.; Miller, Karl, V.; Pearson, Scott, F.

    2002-01-01

    Wildlife-habitat relationships models are used widely by land managers to provide information on which species are likely to occur in an area of interest and may be impacted by a proposed management activity. Few such models have been tested. Recent Avian census data from the Savannah River Site, South Carolina was used to validate BIRDHAB, a geographic information system (GIS) model developed by United States Forest Service resource managers to predict relative habitat quality for birds at the stand level on national forests in the southeastern United States. BIRDHAB is based on the species-habitat matrices presented by Hamel (1992).

  9. Synthesis, characterization and molecular modelling of a novel dipyridamole supramolecule - X-ray structure, quantum mechanics and molecular dynamics study to comprehend the hydrogen bond structure-activity relationship

    NASA Astrophysics Data System (ADS)

    Vepuri, Suresh B.; Devarajegowda, H. C.; Soliman, Mahmoud E.

    2016-02-01

    Hydrochloride salt formation for Active Pharmaceutical Ingredients (APIs) is the primary choice to impart aqueous solubility and to promote dissolution. Dipyridamole (DIP) is a cardiovascular drug which is practically insoluble in water. We discovered a new form of DIP called as dipyridamole hydrochloride trihydrate (DIPHT), which was prepared by an unusual method of reacting the DIP with hydrated hydrochloric acid (HCl) that was liberated in situ by the reaction of ferric chloride with water. The liberated HCl was consumed as reagent in situ by the scavenger (API) and was converted to a hydrochloride trihydrate. The product was characterized by FTIR, mass spectroscopy, PXRD and DSC. Supramolecular structure of this novel DIPHT was revealed by single crystal XRD. A sustained intramolecular hydrogen bond alliance was found in DIP and the DIPHT. Stability of this hydrogen bond was further evaluated by means of molecular modelling studies. We performed electron calculations using quantum mechanics (QM) on both the base and salt structures to compare their geometry and molecular orbital energy levels. Molecular Dynamics (MD) simulations were also conducted in explicit solvent models to provide more insights into the hydrogen bond strength and conformational preferences of the base and salt structure. Together with QM and MD, we were able to explain the influence of hydrogen bonds on proton uptake activity of DIP and stability of DIP and DIPHT. DIPHT which can dissolve faster than DIP in water may enhance the dissolution and bioavailability of the drug. As the current drug development research is shifting to repurpose the existing drugs in order to subside the untoward risks in new drug development, we believe that DIPHT with its intrinsic aqueous solubility could bring more application for DIP and generate interest within the pharmaceutical industry.

  10. Three dimensional quantitative structure-activity relationships of sulfonamides binding monoclonal antibody by comparative molecular field analysis

    Technology Transfer Automated Retrieval System (TEKTRAN)

    The three-dimensional quantitative structure-activity relationship (3D-QSAR) model of sulfonamide analogs, binding a monoclonal antibody (MabSMR) produced against sulfamerazine was carried out by comparative molecular field analysis (CoMFA). The affinities of MabSMR, expressed as Log10IC50, for 17 ...

  11. Dose–response relationship between sports activity and musculoskeletal pain in adolescents

    PubMed Central

    Kamada, Masamitsu; Abe, Takafumi; Kitayuguchi, Jun; Imamura, Fumiaki; Lee, I-Min; Kadowaki, Masaru; Sawada, Susumu S.; Miyachi, Motohiko; Matsui, Yuzuru; Uchio, Yuji

    2016-01-01

    Abstract Physical activity has multiple health benefits but may also increase the risk of developing musculoskeletal pain (MSP). However, the relationship between physical activity and MSP has not been well characterized. This study examined the dose–response relationship between sports activity and MSP among adolescents. Two school-based serial surveys were conducted 1 year apart in adolescents aged 12 to 18 years in Unnan, Japan. Self-administered questionnaires were completed by 2403 students. Associations between time spent in organized sports activity and MSP were analyzed cross-sectionally (n = 2403) and longitudinally (n = 374, students free of pain and in seventh or 10th grade at baseline) with repeated-measures Poisson regression and restricted cubic splines, with adjustment for potential confounders. The prevalence of overall pain, defined as having pain recently at least several times a week in at least one part of the body, was 27.4%. In the cross-sectional analysis, sports activity was significantly associated with pain prevalence. Each additional 1 h/wk of sports activity was associated with a 3% higher probability of having pain (prevalence ratio = 1.03, 95% confidence interval = 1.02-1.04). Similar trends were found across causes (traumatic and nontraumatic pain) and anatomic locations (upper limbs, lower back, and lower limbs). In longitudinal analysis, the risk ratio for developing pain at 1-year follow-up per 1 h/wk increase in baseline sports activity was 1.03 (95% confidence interval = 1.02-1.05). Spline models indicated a linear association (P < 0.001) but not a nonlinear association (P ≥ 0.45). The more the adolescents played sports, the more likely they were to have and develop pain. PMID:26894915

  12. Structure-activity relationship of synthetic branched-chain distearoylglycerol (distearin) as protein kinase C activators

    SciTech Connect

    Zhou, Qingzhong; Raynor, R.L.; Wood, M.G. Jr.; Menger, F.M.; Kuo, J.F. )

    1988-09-20

    Several representative branched-chain analogues of distearin (DS) were synthesized and tested for their abilities to activate protein kinase C (PKC) and to compete for the binding of ({sup 3}H)phorbol 12,13-dibutyrate (PDBu) to the enzyme. Substitutions of stearoyl moieties at sn-1 and sn-2 with 8-methylstearate decreased activities on these parameters, relative to those of the parental diacylglycerol DS, a weak PKC activator. Substitutions with 8-butyl, 4-butyl, or 8-phenyl derivatives, on the other hand, increased activities of the resulting analogues to levels comparable to those seen for diolein (DO), a diacylglycerol prototype shown to be a potent PKC activator. Kinetic analysis indicated that 8-methyldistearin (8-MeDS) acted by decreasing, whereas 8-butyldistearin (8-BuDS) and 8-phenyldistearin (8-PhDS) acted by increasing, the affinities of PKC for phosphatidylserine (PS, a phospholipid cofactor) and Ca{sup 2+} compared to the values seen in the absence or presence of DS. The stimulatory effect of 8-BuDS and 8-PhDS on PKC, as DO, was additive to that of 1,2-(8-butyl)distearoylphosphatidylcholine (1,2(8-Bu)DSPC) and, moreover, they abolished the marked inhibition of the enzyme activity caused by high concentrations of 1,2(8-Bu)DSPC. The present findings demonstrated a structure-activity relationship of the branched-chain DS analogues in the regulation of PKC, perhaps related to their abilities to specifically modify interactions of PKC with PS and/or Ca{sup 2+} critically involved in enzyme activation/inactivation.

  13. Moderators of the Relationship between Physical Activity and Alcohol Consumption in College Students

    ERIC Educational Resources Information Center

    Buscemi, Joanna; Martens, Matthew P.; Murphy, James G.; Yurasek, Ali M.; Smith, Ashley E.

    2011-01-01

    Objective: Among college students, several studies have found a positive relationship between physical activity and alcohol use. The current study tested gender, Greek status, and ethnicity as potential moderators of the physical activity-alcohol use relationship. Participants: Participants were college freshmen (n = 310) endorsing alcohol/drug…

  14. Adolescents' Perception of the Relationship between Movement Skills, Physical Activity and Sport

    ERIC Educational Resources Information Center

    Barnett, Lisa; Cliff, Ken; Morgan, Philip; van Beurden, Eric

    2013-01-01

    Movement skill competence is important to organised youth physical activity participation, but it is unclear how adolescents view this relationship. The primary aim of this study was to explore adolescents' perception of the relationship between movement skills, physical activity and sport, and whether their perceptions differed according to…

  15. Relationship Status and Activated Kin Support: The Role of Need and Norms

    ERIC Educational Resources Information Center

    Mazelis, Joan Maya; Mykyta, Laryssa

    2011-01-01

    Using data from the Fragile Families and Child Wellbeing Study, we examined whether mothers' (N = 4,127) and fathers' (N = 3,405) relationship status influenced their activation of financial support from relatives over time. We found that relationship status influenced the activation of financial support from relatives but that the effects…

  16. An Examination of the Relationship between Enjoyment, Physical Education, Physical Activity and Health in Irish Adolescents

    ERIC Educational Resources Information Center

    Woods, Catherine B.; Tannehill, Deborah; Walsh, Julia

    2012-01-01

    Enjoyment of physical activity (EPA) is positively correlated with activity, yet little is known of its relationship with enjoyment of physical education (EPE). This study's purpose was to explore EPE and its relationship to EPA. Cross-sectional data (N = 4122, average age 14.5 plus or minus 1.7 years, 48% male) were collected as part of the CSPPA…

  17. The Relationship between Traits of Creativity and Physical Activity in the Elderly.

    ERIC Educational Resources Information Center

    Malone, Harry Nevin

    The purpose of this study was to determine if a relationship exists between traits of creativity in the elderly and their level of physical activity. Another purpose was to determine if there was a relationship between traits of creativity focusing on arousal, sensation-seeking, and playfulness and activity. The study used an ex post facto…

  18. Relationship between Frequency and Intensity of Physical Activity and Health Behaviors of Adolescents

    ERIC Educational Resources Information Center

    Delisle, Tony T.; Werch, Chudley E.; Wong, Alvin H.; Bian, Hui; Weiler, Robert

    2010-01-01

    Background: While studies have determined the importance of physical activity in advancing health outcomes, relatively few have explored the relationship between exercise and various health behaviors of adolescents. The purpose of this study is to examine the relationship between frequency and intensity of physical activity and both health risk…

  19. Study of the relationship between solar activity and terrestrial weather

    NASA Technical Reports Server (NTRS)

    Sturrock, P. A.; Brueckner, G. E.; Dickinson, R. E.; Fukuta, N.; Lanzerotti, L. J.; Lindzen, R. S.; Park, C. G.; Wilcox, J. M.

    1976-01-01

    Evidence for some connection between weather and solar related phenomena is presented. Historical data of world wide temperature variations with relationship to change in solar luminosity are examined. Several test methods for estimating the statistical significance of such phenomena are discussed in detail.

  20. Structure-activity relationship of caffeoylquinic acids on the accelerating activity on ATP production.

    PubMed

    Miyamae, Yusaku; Kurisu, Manami; Han, Junkyu; Isoda, Hiroko; Shigemori, Hideyuki

    2011-01-01

    Caffeoylquinic acid (CQA) is one of the phenylpropanoids which have various bioactivities such as antioxidant, antibacterial, anticancer, antihistamic, and other biological effects. We previously reported that 3,5-di-O-caffeoylquinic acid inhibited amyloid β(1-42)-induced cellular toxicity on human neuroblastoma SH-SY5Y cells and increased the mRNA expression level of glycolytic enzymes and the intracellular ATP level. To investigate structure-activity relationship on the accelerating activity on ATP production, we synthesized 1,4,5-tri-O-caffeoylquinic acid, 4,5-di-O-caffeoylquinic acid, 3,4,5-tri-O-caffeoylquinic acid, and other derivatives. Additionally, we evaluated intracellular ATP level in SH-SY5Y treated with each CQA derivative. As a result, 3,4,5-tri-O-caffeoylquinic acid showed the highest accelerating activity on ATP production among tested compounds. It was suggested that caffeoyl groups bound to quinic acid are important for activity and the more caffeoyl groups are bound to quinic acid, the higher accelerating activity on ATP production exhibits.

  1. The relationship between particulate pollution levels in Australian cities, meteorology, and landscape fire activity detected from MODIS hotspots.

    PubMed

    Price, Owen F; Williamson, Grant J; Henderson, Sarah B; Johnston, Fay; Bowman, David M J S

    2012-01-01

    Smoke from bushfires is an emerging issue for fire managers because of increasing evidence for its public health effects. Development of forecasting models to predict future pollution levels based on the relationship between bushfire activity and current pollution levels would be a useful management tool. As a first step, we use daily thermal anomalies detected by the MODIS Active Fire Product (referred to as "hotspots"), pollution concentrations, and meteorological data for the years 2002 to 2008, to examine the statistical relationship between fire activity in the landscapes and pollution levels around Perth and Sydney, two large Australian cities. Resultant models were statistically significant, but differed in their goodness of fit and the distance at which the strength of the relationship was strongest. For Sydney, a univariate model for hotspot activity within 100 km explained 24% of variation in pollution levels, and the best model including atmospheric variables explained 56% of variation. For Perth, the best radius was 400 km, explaining only 7% of variation, while the model including atmospheric variables explained 31% of the variation. Pollution was higher when the atmosphere was more stable and in the presence of on-shore winds, whereas there was no effect of wind blowing from the fires toward the pollution monitors. Our analysis shows there is a good prospect for developing region-specific forecasting tools combining hotspot fire activity with meteorological data.

  2. The Relationship between Particulate Pollution Levels in Australian Cities, Meteorology, and Landscape Fire Activity Detected from MODIS Hotspots

    PubMed Central

    Price, Owen F.; Williamson, Grant J.; Henderson, Sarah B.; Johnston, Fay; Bowman, David M. J. S.

    2012-01-01

    Smoke from bushfires is an emerging issue for fire managers because of increasing evidence for its public health effects. Development of forecasting models to predict future pollution levels based on the relationship between bushfire activity and current pollution levels would be a useful management tool. As a first step, we use daily thermal anomalies detected by the MODIS Active Fire Product (referred to as “hotspots”), pollution concentrations, and meteorological data for the years 2002 to 2008, to examine the statistical relationship between fire activity in the landscapes and pollution levels around Perth and Sydney, two large Australian cities. Resultant models were statistically significant, but differed in their goodness of fit and the distance at which the strength of the relationship was strongest. For Sydney, a univariate model for hotspot activity within 100 km explained 24% of variation in pollution levels, and the best model including atmospheric variables explained 56% of variation. For Perth, the best radius was 400 km, explaining only 7% of variation, while the model including atmospheric variables explained 31% of the variation. Pollution was higher when the atmosphere was more stable and in the presence of on-shore winds, whereas there was no effect of wind blowing from the fires toward the pollution monitors. Our analysis shows there is a good prospect for developing region-specific forecasting tools combining hotspot fire activity with meteorological data. PMID:23071788

  3. Flavonoids as CDK1 Inhibitors: Insights in Their Binding Orientations and Structure-Activity Relationship.

    PubMed

    Navarro-Retamal, Carlos; Caballero, Julio

    2016-01-01

    In the last years, the interactions of flavonoids with protein kinases (PKs) have been described by using crystallographic experiments. Interestingly, different orientations have been found for one flavonoid inside different PKs and different chemical substitutions lead to different orientations of the flavonoid scaffold inside one PK. Accordingly, orientation predictions of novel analogues could help to the design of flavonoids with high PK inhibitory activities. With this in mind, we studied the binding modes of 37 flavonoids (flavones and chalcones) inside the cyclin-dependent PK CDK1 using docking experiments. We found that the compounds under study adopted two different orientations into the active site of CDK1 (orientations I and II in the manuscript). In addition, quantitative structure-activity relationship (QSAR) models using CoMFA and CoMSIA methodologies were constructed to explain the trend of the CDK1 inhibitory activities for the studied flavonoids. Template-based and docking-based alignments were used. Models developed starting from docking-based alignment were applied for describing the whole dataset and compounds with orientation I. Adequate R2 and Q2 values were obtained by each method; interestingly, only hydrophobic and hydrogen bond donor fields describe the differential potency of the flavonoids as CDK1 inhibitors for both defined alignments and subsets. Our current application of docking and QSAR together reveals important elements to be drawn for the design of novel flavonoids with increased PK inhibitory activities. PMID:27517610

  4. Docking and quantitative structure-activity relationship of oxadiazole derivates as inhibitors of GSK3β.

    PubMed

    Quesada-Romero, Luisa; Caballero, Julio

    2014-02-01

    The binding modes of 42 oxadiazole derivates inside glycogen synthase kinase 3 beta (GSK3β were determined using docking experiments; thus, the preferred active conformations of these inhibitors are proposed. We found that these compounds adopt a scorpion-shaped conformation and they accept a hydrogen bond (HB) from the residue Val135 of the GSK3β ATP-binding site hinge region. In addition, quantitative structure-activity relationship (QSAR) models were constructed to explain the trend of the GSK3β inhibitory activities for the studied compounds. In a first approach, three-dimensional (3D) vectors were calculated using docking conformations and, by using multiple-linear regression, we assessed that GETAWAY vectors were able to describe the reported biological activities. In other QSAR approach, SMILES-based optimal descriptors were calculated. The best model included three-SMILES elements SSSβ leading to the identification of key molecular features that contribute to a high GSK3β inhibitory activity.

  5. Docking and quantitative structure-activity relationship of oxadiazole derivates as inhibitors of GSK3β.

    PubMed

    Quesada-Romero, Luisa; Caballero, Julio

    2014-02-01

    The binding modes of 42 oxadiazole derivates inside glycogen synthase kinase 3 beta (GSK3β were determined using docking experiments; thus, the preferred active conformations of these inhibitors are proposed. We found that these compounds adopt a scorpion-shaped conformation and they accept a hydrogen bond (HB) from the residue Val135 of the GSK3β ATP-binding site hinge region. In addition, quantitative structure-activity relationship (QSAR) models were constructed to explain the trend of the GSK3β inhibitory activities for the studied compounds. In a first approach, three-dimensional (3D) vectors were calculated using docking conformations and, by using multiple-linear regression, we assessed that GETAWAY vectors were able to describe the reported biological activities. In other QSAR approach, SMILES-based optimal descriptors were calculated. The best model included three-SMILES elements SSSβ leading to the identification of key molecular features that contribute to a high GSK3β inhibitory activity. PMID:24081608

  6. Flavonoids as CDK1 Inhibitors: Insights in Their Binding Orientations and Structure-Activity Relationship

    PubMed Central

    Navarro-Retamal, Carlos

    2016-01-01

    In the last years, the interactions of flavonoids with protein kinases (PKs) have been described by using crystallographic experiments. Interestingly, different orientations have been found for one flavonoid inside different PKs and different chemical substitutions lead to different orientations of the flavonoid scaffold inside one PK. Accordingly, orientation predictions of novel analogues could help to the design of flavonoids with high PK inhibitory activities. With this in mind, we studied the binding modes of 37 flavonoids (flavones and chalcones) inside the cyclin-dependent PK CDK1 using docking experiments. We found that the compounds under study adopted two different orientations into the active site of CDK1 (orientations I and II in the manuscript). In addition, quantitative structure–activity relationship (QSAR) models using CoMFA and CoMSIA methodologies were constructed to explain the trend of the CDK1 inhibitory activities for the studied flavonoids. Template-based and docking-based alignments were used. Models developed starting from docking-based alignment were applied for describing the whole dataset and compounds with orientation I. Adequate R2 and Q2 values were obtained by each method; interestingly, only hydrophobic and hydrogen bond donor fields describe the differential potency of the flavonoids as CDK1 inhibitors for both defined alignments and subsets. Our current application of docking and QSAR together reveals important elements to be drawn for the design of novel flavonoids with increased PK inhibitory activities. PMID:27517610

  7. Structure-thermodynamics-antioxidant activity relationships of selected natural phenolic acids and derivatives: an experimental and theoretical evaluation.

    PubMed

    Chen, Yuzhen; Xiao, Huizhi; Zheng, Jie; Liang, Guizhao

    2015-01-01

    Phenolic acids and derivatives have potential biological functions, however, little is known about the structure-activity relationships and the underlying action mechanisms of these phenolic acids to date. Herein we investigate the structure-thermodynamics-antioxidant relationships of 20 natural phenolic acids and derivatives using DPPH• scavenging assay, density functional theory calculations at the B3LYP/6-311++G(d,p) levels of theory, and quantitative structure-activity relationship (QSAR) modeling. Three main working mechanisms (HAT, SETPT and SPLET) are explored in four micro-environments (gas-phase, benzene, water and ethanol). Computed thermodynamics parameters (BDE, IP, PDE, PA and ETE) are compared with the experimental radical scavenging activities against DPPH•. Available theoretical and experimental investigations have demonstrated that the extended delocalization and intra-molecular hydrogen bonds are the two main contributions to the stability of the radicals. The C = O or C = C in COOH, COOR, C = CCOOH and C = CCOOR groups, and orthodiphenolic functionalities are shown to favorably stabilize the specific radical species to enhance the radical scavenging activities, while the presence of the single OH in the ortho position of the COOH group disfavors the activities. HAT is the thermodynamically preferred mechanism in the gas phase and benzene, whereas SPLET in water and ethanol. Furthermore, our QSAR models robustly represent the structure-activity relationships of these explored compounds in polar media. PMID:25803685

  8. Structure-thermodynamics-antioxidant activity relationships of selected natural phenolic acids and derivatives: an experimental and theoretical evaluation.

    PubMed

    Chen, Yuzhen; Xiao, Huizhi; Zheng, Jie; Liang, Guizhao

    2015-01-01

    Phenolic acids and derivatives have potential biological functions, however, little is known about the structure-activity relationships and the underlying action mechanisms of these phenolic acids to date. Herein we investigate the structure-thermodynamics-antioxidant relationships of 20 natural phenolic acids and derivatives using DPPH• scavenging assay, density functional theory calculations at the B3LYP/6-311++G(d,p) levels of theory, and quantitative structure-activity relationship (QSAR) modeling. Three main working mechanisms (HAT, SETPT and SPLET) are explored in four micro-environments (gas-phase, benzene, water and ethanol). Computed thermodynamics parameters (BDE, IP, PDE, PA and ETE) are compared with the experimental radical scavenging activities against DPPH•. Available theoretical and experimental investigations have demonstrated that the extended delocalization and intra-molecular hydrogen bonds are the two main contributions to the stability of the radicals. The C = O or C = C in COOH, COOR, C = CCOOH and C = CCOOR groups, and orthodiphenolic functionalities are shown to favorably stabilize the specific radical species to enhance the radical scavenging activities, while the presence of the single OH in the ortho position of the COOH group disfavors the activities. HAT is the thermodynamically preferred mechanism in the gas phase and benzene, whereas SPLET in water and ethanol. Furthermore, our QSAR models robustly represent the structure-activity relationships of these explored compounds in polar media.

  9. Modeling temporal relationships in large scale clinical associations

    PubMed Central

    Hanauer, David A; Ramakrishnan, Naren

    2013-01-01

    Objective We describe an approach for modeling temporal relationships in a large scale association analysis of electronic health record data. The addition of temporal information can inform hypothesis generation and help to explain the relationships. We applied this approach on a dataset containing 41.2 million time-stamped International Classification of Diseases, Ninth Revision (ICD-9) codes from 1.6 million patients. Methods We performed two independent analyses including a pairwise association analysis using a χ2 test and a temporal analysis using a binomial test. Data were visualized using network diagrams and reviewed for clinical significance. Results We found nearly 400 000 highly associated pairs of ICD-9 codes with varying numbers of strong temporal associations ranging from ≥1 day to ≥10 years apart. Most of the findings were not considered clinically novel, although some, such as an association between Helicobacter pylori infection and diabetes, have recently been reported in the literature. The temporal analysis in our large cohort, however, revealed that diabetes usually preceded the diagnoses of H pylori, raising questions about possible cause and effect. Discussion Such analyses have significant limitations, some of which are due to known problems with ICD-9 codes and others to potentially incomplete data even at a health system level. Nevertheless, large scale association analyses with temporal modeling can help provide a mechanism for novel discovery in support of hypothesis generation. Conclusions Temporal relationships can provide an additional layer of meaning in identifying and interpreting clinical associations. PMID:23019240

  10. Models of physician-patient relationships in pharmaceutical direct-to-consumer advertising and consumer interviews.

    PubMed

    Arney, Jennifer; Lewin, Benjamin

    2013-07-01

    The rise of direct-to-consumer advertising (DTCA) has mirrored, if not facilitated, the shift toward more active health care consumers. We used content analysis to identify models of physician-patient interaction in DTCA from the 1997 to 2006 issues of a broad sample of women's, men's, and common readership magazines. We also conducted 36 in-depth interviews to examine the ways consumers receive and regard advertising messages, and to explore their preferences for clinical communication and decision making. We identified four models of physician-patient relationships that vary in their locus of control (physician, patient, or shared) and the form of support sought or obtained in the relationship (emotional or instrumental). Whereas consumer interviews reflected references to all four models of interaction, only two appeared in DTCA. The limited range of interactions seen in these advertisements creates a lack of congruity between interaction styles found in advertisements vs. styles reported by actual consumers. PMID:23645149

  11. The coach-athlete relationship: a motivational model.

    PubMed

    Mageau, Geneviève A; Vallerand, Robert J

    2003-11-01

    The aim of this paper is to present a motivational model of the coach-athlete relationship that describes how coaches may influence athletes' motivation. In line with cognitive evaluation theory (Deci and Ryan, 1980, 1985) and the hierarchical model of intrinsic and extrinsic motivation (Vallerand, 1997, 2000), a motivational sequence is proposed where coaches' personal orientation towards coaching, the context within which they operate, and their perceptions of their athletes' behaviour and motivation influence coaches' behaviours. Also, coaches' behaviours in the form of autonomy-supportive behaviours, provision of structure and involvement have a beneficial impact on athletes' needs for autonomy, competence and relatedness, which, in turn, nurture athletes' intrinsic motivation and self-determined types of extrinsic motivation. Here, we first review coaches' autonomy-supportive behaviours. We then describe the psychological processes through which coaching behaviours have a positive influence on athletes' intrinsic and self-determined extrinsic motivation. Finally, we identify social and personality processes that determine coaching behaviours.

  12. Shared social and emotional activities within adolescent romantic and non-romantic sexual relationships.

    PubMed

    Williams, Lela Rankin; Russell, Stephen T

    2013-05-01

    Typically, "non-romantic" sexual relationships are assumed to be casual; however, the emotional and social distinctions between romantic and non-romantic contexts are not well understood, particularly in adolescence. Data from the National Longitudinal Study of Adolescent Health (Add Health) was used to compare shared emotional (e.g., telling partner that they love her/him) and social (e.g., going out in a group) activities within romantic and non-romantic sexual relationships. Adolescents who reported exclusively romantic sexual relationships (n = 1,891) shared more emotional, but not social, activities with their partners than adolescents who were in non-romantic sexual relationships (n = 315; small effect size, r = .07-.13), akin to adolescents who experienced both relationship types (n = 519; small-to-medium effect size, r = .18-.38). Girls shared more emotional and social activities with their partners than boys when in romantic relationships (small effect size, r = .06-.10); there were no significant gender differences within non-romantic sexual relationships. Findings suggest that gendered scripts remain for sexual relationships that are romantic but not for those that are non-romantic. Notably, for the majority of adolescents, non-romantic relationships still held many emotional and social dimensions typical of romantic relationships and differences between relationship types were small. Although non-romantic relationships were less intimate than romantic sexual relationships, there was remarkable heterogeneity within this relationship type. Caution is advised when working with adolescents engaged in "casual" sexual relationships. Understanding the complexity of adolescent sexual relationships is critical for the advancement of effective sex education programming.

  13. Relationship Characteristics Associated with the Experience of Hurt in Romantic Relationships: A Test of the Relational Turbulence Model

    ERIC Educational Resources Information Center

    Theiss, Jennifer A.; Knobloch, Leanne K.; Checton, Maria G.; Magsamen-Conrad, Kate

    2009-01-01

    We employed the relational turbulence model to identify (a) relationship characteristics associated with people's appraisals of hurtful messages, and (b) features of hurtful episodes and relationship characteristics that correspond with the directness of communication about hurt. We conducted a study in which 135 dating couples reported on their…

  14. Relationship between anticoagulant activities and polyanionic properties of rabbit thrombomodulin.

    PubMed

    Bourin, M C; Ohlin, A K; Lane, D A; Stenflo, J; Lindahl, U

    1988-06-15

    Rabbit thrombomodulin displays three distinct blood anticoagulant activities: it promotes the activation of protein C by thrombin (protein C activation cofactor activity); it promotes the inactivation of thrombin by thrombin (direct anticoagulant activity). The effects on these activities of mouse anti-thrombomodulin monoclonal antibodies and of the heparin-neutralizing proteins, platelet factor 4, histidine-rich glycoprotein, and S-protein, were investigated. One of the antibodies, which did not influence the functional properties of thrombomodulin, was used as an immunoaffinity ligand for purification of the protein. Two other antibodies, which were found to abrogate the protein C activation cofactor activity of the purified thrombomodulin, also abolished the antithrombin-dependent and the direct anticoagulant activities. The heparin-neutralizing proteins all inhibited the two latter activities, albeit to a varying extent, but did not appreciably affect the activation of protein C. These results are interpreted in relation to our previous finding that rabbit thrombomodulin contains an acidic domain, tentatively identified as a sulfated glycosaminoglycan (Bourin, M.-C., Boffa, M.-C., Björk, I., and Lindahl, U. (1986) Proc. Natl. Acad. Sci. U.S.A. 83, 5924-5928). It is proposed that the acidic domain interacts with thrombin at the protein C activation site and that this interaction is a prerequisite to the expression of direct as well as antithrombin-dependent anticoagulant activity. The interaction is not essential to, but compatible with, the activation of protein C. Experiments involving treatment of thrombomodulin with various glycanases or with nitrous acid, followed by measurement of anticoagulant activities, indicated that the acidic domain is constituted by a sulfated galactosaminoglycan and not by a heparin-related polysaccharide as previously suggested.

  15. Inhibition of Angiotensin-Converting Enzyme Activity by Flavonoids: Structure-Activity Relationship Studies

    PubMed Central

    Guerrero, Ligia; Castillo, Julián; Quiñones, Mar; Garcia-Vallvé, Santiago; Arola, Lluis; Pujadas, Gerard; Muguerza, Begoña

    2012-01-01

    Previous studies have demonstrated that certain flavonoids can have an inhibitory effect on angiotensin-converting enzyme (ACE) activity, which plays a key role in the regulation of arterial blood pressure. In the present study, 17 flavonoids belonging to five structural subtypes were evaluated in vitro for their ability to inhibit ACE in order to establish the structural basis of their bioactivity. The ACE inhibitory (ACEI) activity of these 17 flavonoids was determined by fluorimetric method at two concentrations (500 µM and 100 µM). Their inhibitory potencies ranged from 17 to 95% at 500 µM and from 0 to 57% at 100 µM. In both cases, the highest ACEI activity was obtained for luteolin. Following the determination of ACEI activity, the flavonoids with higher ACEI activity (i.e., ACEI >60% at 500 µM) were selected for further IC50 determination. The IC50 values for luteolin, quercetin, rutin, kaempferol, rhoifolin and apigenin K were 23, 43, 64, 178, 183 and 196 µM, respectively. Our results suggest that flavonoids are an excellent source of functional antihypertensive products. Furthermore, our structure-activity relationship studies show that the combination of sub-structures on the flavonoid skeleton that increase ACEI activity is made up of the following elements: (a) the catechol group in the B-ring, (b) the double bond between C2 and C3 at the C-ring, and (c) the cetone group in C4 at the C-ring. Protein-ligand docking studies are used to understand the molecular basis for these results. PMID:23185345

  16. Inhibition of Cancer-Associated Mutant Isocitrate Dehydrogenases: Synthesis, Structure–Activity Relationship, and Selective Antitumor Activity

    PubMed Central

    2015-01-01

    Mutations of isocitrate dehydrogenase 1 (IDH1) are frequently found in certain cancers such as glioma. Different from the wild-type (WT) IDH1, the mutant enzymes catalyze the reduction of α-ketoglutaric acid to d-2-hydroxyglutaric acid (D2HG), leading to cancer initiation. Several 1-hydroxypyridin-2-one compounds were identified to be inhibitors of IDH1(R132H). A total of 61 derivatives were synthesized, and their structure–activity relationships were investigated. Potent IDH1(R132H) inhibitors were identified with Ki values as low as 140 nM, while they possess weak or no activity against WT IDH1. Activities of selected compounds against IDH1(R132C) were found to be correlated with their inhibitory activities against IDH1(R132H), as well as cellular production of D2HG, with R2 of 0.83 and 0.73, respectively. Several inhibitors were found to be permeable through the blood–brain barrier in a cell-based model assay and exhibit potent and selective activity (EC50 = 0.26–1.8 μM) against glioma cells with the IDH1 R132H mutation. PMID:25271760

  17. Relationship between mean body temperature calculated by two- or three-compartment models and active cutaneous vasodilation in humans: a comparison between cool and warm environments during leg exercise.

    PubMed

    Demachi, Koichi; Yoshida, Tetsuya; Tsuneoka, Hideyuki

    2012-03-01

    The aim of this study was to assess whether the three-compartment model of mean body temperature (Tb3) calculated from the esophageal temperature (Tes), temperature in deep tissue of exercising muscle (Tdt), and mean skin temperature (Tsk) has the potential to provide a better match with the thermoregulatory responses than the two-component model of mean body temperature (Tb2) calculated from Tes and Tsk. Seven male subjects performed 40 min of a prolonged cycling exercise at 30% maximal oxygen uptake at 21°C or 31°C (50% relative humidity). Throughout the experiment, Tsk, Tb2, Tb3, and Tdt were significantly (P < 0.01) lower at 21°C than at 31°C temperature conditions, while Tes was similar under both conditions. During exercise, an increase in cutaneous vascular conductance (skin blood flow / mean arterial pressure) over the chest (%CVCc) was observed at both 21°C and 31°C, while no increase was observed at the forearm at 21°C. Furthermore, the Tb3 and Tdt threshold for the onset of the increase in %CVCc was similar, but the Tes and Tb2 threshold differed significantly (P < 0.05) between the conditions tested. These results suggest that active cutaneous vasodilation at the chest is related more closely to Tb3 or Tdt than that measured by Tes or Tb2 calculated by Tes and Tsk during exercise at both 21°C and 31°C.

  18. Design, structure activity relationship, cytotoxicity and evaluation of antioxidant activity of curcumin derivatives/analogues.

    PubMed

    Sahu, Pramod K

    2016-10-01

    New fourteen 3,4-dihydropyrimidine derivatives/analogues of curcumin (2a-2n) were designed, synthesized and biologically evaluated for their cytotoxicity and antioxidant activity. Cytotoxicity effect has been evaluated against three cell lines HeLa, HCT-116 and QG-56 by MTT assay method. From SAR study, it has been revealed that particularly, compound 2e and 2j (IC50 value 12.5 μM) have shown better cytotoxicity effect against three cell lines. According to results of SAR study, it was found that 3,4-dihydropyrimidines of curcumin, 2c, 2d, 2j and 2n exhibited better antioxidant activity than curcumin. A correlation of structure and activities relationship of these compounds with respect to drug score profiles and other physico-chemical properties of drugs are described and verified experimentally. Therefore, we conclude that physico-chemical analyses may prove structural features of curcumin analogues with their promising combined cytotoxicity/antioxidant activity and it is also concluded from virtual and practical screening that the compounds were varied to possess a broad range of lipophilic character, revealed by Log P values. PMID:27318975

  19. Biophysical properties of Saccharomyces cerevisiae and their relationship with HOG pathway activation

    PubMed Central

    Adrover, Miquel Àngel; Eriksson, Emma; Pelet, Serge; Petelenz-Kurdziel, Elzbieta; Klein, Dagmara; Posas, Francesc; Goksör, Mattias; Peter, Mathias; Hohmann, Stefan

    2010-01-01

    Parameterized models of biophysical and mechanical cell properties are important for predictive mathematical modeling of cellular processes. The concepts of turgor, cell wall elasticity, osmotically active volume, and intracellular osmolarity have been investigated for decades, but a consistent rigorous parameterization of these concepts is lacking. Here, we subjected several data sets of minimum volume measurements in yeast obtained after hyper-osmotic shock to a thermodynamic modeling framework. We estimated parameters for several relevant biophysical cell properties and tested alternative hypotheses about these concepts using a model discrimination approach. In accordance with previous reports, we estimated an average initial turgor of 0.6 ± 0.2 MPa and found that turgor becomes negligible at a relative volume of 93.3 ± 6.3% corresponding to an osmotic shock of 0.4 ± 0.2 Osm/l. At high stress levels (4 Osm/l), plasmolysis may occur. We found that the volumetric elastic modulus, a measure of cell wall elasticity, is 14.3 ± 10.4 MPa. Our model discrimination analysis suggests that other thermodynamic quantities affecting the intracellular water potential, for example the matrix potential, can be neglected under physiological conditions. The parameterized turgor models showed that activation of the osmosensing high osmolarity glycerol (HOG) signaling pathway correlates with turgor loss in a 1:1 relationship. This finding suggests that mechanical properties of the membrane trigger HOG pathway activation, which can be represented and quantitatively modeled by turgor. Electronic supplementary material The online version of this article (doi:10.1007/s00249-010-0612-0) contains supplementary material, which is available to authorized users. PMID:20563574

  20. In Vivo Structure-Activity Relationship Studies Support Allosteric Targeting of a Dual Specificity Phosphatase

    PubMed Central

    Korotchenko, Vasiliy N.; Saydmohammed, Manush; Vollmer, Laura L.; Bakan, Ahmet; Sheetz, Kyle; Debiec, Karl T.; Greene, Kristina A.; Agliori, Christine S.; Bahar, Ivet; Day, Billy W.; Vogt, Andreas; Tsang, Michael

    2014-01-01

    Dual specificity phosphatase 6 (DUSP6) functions as a feedback attenuator of Fibroblast Growth Factor signaling during development. In vitro high throughput chemical screening attempts to discover DUSP6 inhibitors have yielded limited success. Yet, in vivo whole organism screens using zebrafish identified 1 (BCI) as an allosteric inhibitor of DUSP6. Here we designed and synthesized a panel of analogs to define structure-activity relationship (SAR) of DUSP6 inhibition. In vivo, high-content analysis in transgenic zebrafish coupled with cell-based chemical complementation assays identified structural features of the 1 pharmacophore that were essential for biological activity. In vitro assays of DUSP hyperactivation corroborated the results from in vivo and cellular SAR. The results reinforce the notion that DUSPs are druggable through allosteric mechanisms, and illustrate the utility of zebrafish as a model organism for in vivo SAR analyses. PMID:24909879

  1. A structure-activity relationship for induction of meningeal inflammation by muramyl peptides.

    PubMed Central

    Burroughs, M; Rozdzinski, E; Geelen, S; Tuomanen, E

    1993-01-01

    Components of bacterial peptidoglycans have potent biological activities, including adjuvant effects, cytotoxicity, and induction of sleep. Mixtures of peptidoglycan components also induce inflammation in the lung, subarachnoid space, and joint, but the structural requirements for activity are unknown. Using a rabbit model for meningitis, we determined the biological activities of 14 individual muramyl peptides constituting > 90% of the peptidoglycan of the gram-negative pediatric pathogen Haemophilus influenzae. Upon intracisternal inoculation, most of the muropeptides induced leukocytosis in cerebrospinal fluid (CSF), influx of protein into CSF, or brain edema, alone or in combination. The disaccharide-tetrapeptide, the major component of all gram-negative peptidoglycans, induced CSF leukocytosis and protein influx at doses as low as 0.4 microgram (0.42 nM). Modification of the N-acetyl muramic acid or substitution of the alanine at position four in the peptide side chain decreased leukocytosis but enhanced brain edema. As the size of the muropeptide increased, the inflammatory activity decreased. Muropeptide carrying the diaminopimelyl-diaminopimelic acid cross-link specifically induced cytotoxic brain edema. These findings significantly expand the spectrum of biological activities of natural muramyl peptides and provide the basis for a structure-activity relationship for the inflammatory properties of bacterial muropeptides. PMID:8325996

  2. The Activity System of School-Teaching Mathematics and Mathematical Modelling.

    ERIC Educational Resources Information Center

    Julie, Cyril

    2002-01-01

    Focuses on the activity system of school-teaching mathematics and the impact of mathematical modeling. Describes the Applications of and Modeling in School Mathematics Project (AMSMAP) which investigates teachers' mathematical modeling and its relationship to a hypothesized school mathematical modeling activity system. Discusses the notion of an…

  3. Early and current physical activity: relationship with intima-media thickness and metabolic variables in adulthood

    PubMed Central

    Lima, Manoel C. S.; Barbosa, Maurício F.; Diniz, Tiego A.; Codogno, Jamile S.; Freitas, Ismael F.; Fernandes, Rômulo A.

    2014-01-01

    Background: It is unclear whether early physical activity has a greater influence on intima-media thickness and metabolic variables than current physical activity. Objective: To analyze the relationship between current and early physical activity, metabolic variables, and intima-media thickness measures in adults. Method: The sample was composed of 55 healthy subjects of both sexes (33 men and 22 women). Total body fat and trunk fat were estimated by dual-energy X-ray absorptiometry. Carotid and femoral intima-media thickness were measured using a Doppler ultrasound device. A 12-hour fasting blood sample collection was taken (fasting glucose and lipid profile). Early physical activity was assessed through face-to-face interview, and the current physical activity was assessed by pedometer (Digi-Walker Yamax, SW200), which was used for a period of seven days. Results: Current physical activity was negatively related to total cholesterol (rho=-0.31), while early physical activity was negatively related to triglycerides (rho=-0.42), total cholesterol (rho=-0.28), very low density lipoprotein (rho=-0.44), and carotid intima-media thickness (rho=-0.50). In the multivariate model, subjects engaged in sports activities during early life had lower values of very low density lipoprotein (b=-8.74 [b=-16.1; -1.47]) and carotid intima-media thickness (b=-0.17 [95%CI: -0.28; -0.05]). Conclusion: Early 95%CI physical activity has a significant influence on carotid intima-media thickness, regardless of the current physical activity. PMID:25372009

  4. Structure-Activity Relationship Analysis of the Thermal Stabilities of Nitroaromatic Compounds Following Different Decomposition Mechanisms.

    PubMed

    Li, Jiazhong; Liu, Huanxiang; Huo, Xing; Gramatica, Paola

    2013-02-01

    The decomposition behavior of energetic materials is very important for the safety problems concerning their production, transportation, use and storage, because molecular decomposition is intimately connected to their explosive properties. Nitroaromatic compounds, particularly nitrobenzene derivatives, are often considered as prototypical energetic molecules, and some of them are commonly used as high explosives. Quantitative structure-activity relationship (QSAR) represents a potential tool for predicting the thermal stability properties of energetic materials. But it is reported that constructing general reliable models to predict their stability and their potential explosive properties is a very difficult task. In this work, we make our efforts to investigate the relationship between the molecular structures and corresponding thermal stabilities of 77 nitrobenzene derivatives with various substituent functional groups (in ortho, meta and/or para positions). The proposed best MLR model, developed by the new software QSARINS, based on Genetic Algorithm for variable selection and with various validation tools, is robust, stable and predictive with R(2) of 0.86, QLOO (2) of 0.79 and CCC of 0.90. The results indicated that, though difficult, it is possible to build predictive, externally validated QSAR models to estimate the thermal stability of nitroaromatic compounds.

  5. TYPE II SUPERNOVAE: MODEL LIGHT CURVES AND STANDARD CANDLE RELATIONSHIPS

    SciTech Connect

    Kasen, Daniel; Woosley, S. E.

    2009-10-01

    A survey of Type II supernovae explosion models has been carried out to determine how their light curves and spectra vary with their mass, metallicity, and explosion energy. The presupernova models are taken from a recent survey of massive stellar evolution at solar metallicity supplemented by new calculations at subsolar metallicity. Explosions are simulated by the motion of a piston near the edge of the iron core and the resulting light curves and spectra are calculated using full multi-wavelength radiation transport. Formulae are developed that describe approximately how the model observables (light curve luminosity and duration) scale with the progenitor mass, explosion energy, and radioactive nucleosynthesis. Comparison with observational data shows that the explosion energy of typical supernovae (as measured by kinetic energy at infinity) varies by nearly an order of magnitude-from 0.5 to 4.0 x 10{sup 51} ergs, with a typical value of approx0.9 x 10{sup 51} ergs. Despite the large variation, the models exhibit a tight relationship between luminosity and expansion velocity, similar to that previously employed empirically to make SNe IIP standardized candles. This relation is explained by the simple behavior of hydrogen recombination in the supernova envelope, but we find a sensitivity to progenitor metallicity and mass that could lead to systematic errors. Additional correlations between light curve luminosity, duration, and color might enable the use of SNe IIP to obtain distances accurate to approx20% using only photometric data.

  6. Design and prediction of new acetylcholinesterase inhibitor via quantitative structure activity relationship of huprines derivatives.

    PubMed

    Zhang, Shuqun; Hou, Bo; Yang, Huaiyu; Zuo, Zhili

    2016-05-01

    Acetylcholinesterase (AChE) is an important enzyme in the pathogenesis of Alzheimer's disease (AD). Comparative quantitative structure-activity relationship (QSAR) analyses on some huprines inhibitors against AChE were carried out using comparative molecular field analysis (CoMFA), comparative molecular similarity indices analysis (CoMSIA), and hologram QSAR (HQSAR) methods. Three highly predictive QSAR models were constructed successfully based on the training set. The CoMFA, CoMSIA, and HQSAR models have values of r (2) = 0.988, q (2) = 0.757, ONC = 6; r (2) = 0.966, q (2) = 0.645, ONC = 5; and r (2) = 0.957, q (2) = 0.736, ONC = 6. The predictabilities were validated using an external test sets, and the predictive r (2) values obtained by the three models were 0.984, 0.973, and 0.783, respectively. The analysis was performed by combining the CoMFA and CoMSIA field distributions with the active sites of the AChE to further understand the vital interactions between huprines and the protease. On the basis of the QSAR study, 14 new potent molecules have been designed and six of them are predicted to be more active than the best active compound 24 described in the literature. The final QSAR models could be helpful in design and development of novel active AChE inhibitors.

  7. Classical Nuclear Hormone Receptor Activity as a Mediator of Complex Concentration Response Relationships for Endocrine Active Compounds

    PubMed Central

    Cookman, Clifford J.; Belcher, Scott M.

    2014-01-01

    Nonmonotonic concentration response relationships are frequently observed for endocrine active ligands that act via nuclear receptors. The curve of best fit for nonmonotonic concentration response relationships are often inverted U-shaped with effects at intermediate concentrations that are different from effects at higher or lower concentrations. Cytotoxicity is a major mode of action responsible for inverted U-shaped concentration response relationships. However, evidence suggests that ligand selectivity, activation of multiple molecular targets, concerted regulation of multiple opposing endpoints, and multiple ligand binding sites within nuclear receptors also contribute to nonmonotonic concentration response relationships of endocrine active ligands. This review reports the current understanding of mechanisms involved in classical nuclear receptor mediated nonmonotonic concentration response relationships with a focus on studies published between 2012 and 2014. PMID:25299165

  8. Evaluation of MRI Models in the Measurement of CMRO2 and Its Relationship With CBF

    PubMed Central

    Lin, Ai-Ling; Fox, Peter T.; Yang, Yihong; Lu, Hanzhang; Tan, Li-Hai; Gao, Jia-Hong

    2008-01-01

    The aim of this study was to investigate the various MRI biophysical models in the measurements of local cerebral metabolic rate of oxygen (CMRO2) and the corresponding relationship with cerebral blood flow (CBF) during brain activation. This aim was addressed by simultaneously measuring the relative changes in CBF, cerebral blood volume (CBV), and blood oxygen level dependent (BOLD) MRI signals in the human visual cortex during visual stimulation. A radial checkerboard delivered flash stimulation at five different frequencies. Two MRI models, the single-compartment model (SCM) and the multi-compartment model (MCM), were used to determine the relative changes in CMRO2 using three methods: [1] SCM with parameters identical to those used in a prior MRI study (M = 0.22; α = 0.38); [2] SCM with directly measured parameters (M from hypercapnia and α from measured δCBV and δCBF); and [3] MCM. The magnitude of relative changes in CMRO2 and the nonlinear relationship between CBF and CMRO2 obtained with Methods [2] and [3] were not in agreement with those obtained using Method [1]. However, the results of Methods [2] and [3] were aligned with positron emission tomography findings from the literature. Our results indicate that if appropriate parameters are used, the SCM and MCM models are equivalent for quantifying the values of CMRO2 and determining the flow-metabolism relationship. PMID:18666102

  9. The relationship between clouds and dynamics in Southern Hemisphere extratropical cyclones in the real world and a climate model

    NASA Astrophysics Data System (ADS)

    Govekar, Pallavi D.; Jakob, Christian; Catto, Jennifer

    2014-06-01

    The representation of clouds over the Southern Ocean in contemporary climate models remains a major challenge. A major dynamical influence on the structure of clouds is the passage of extratropical cyclones. They exert significant dynamical influences on the clouds in the dynamically active frontal regions as well as in the dynamically suppressed regions ahead and behind the cyclones. A cyclone compositing methodology is applied to a reanalysis and vertical profiles of cloudiness from CloudSat/CALIPSO to quantify the relationship between clouds and dynamics in extratropical cyclones over the Southern Ocean. It is found that the range of cloud fraction, vertical motion, and relative humidity changes considerably with height. There is a strong quasi-linear relationship between the three variables which changes with altitude. After establishing the observed relationships, the methodology is applied to the Australian Community Climate and Earth System Simulator to evaluate the model's ability to simulate the identified cloud-dynamics relationships. While the model is able to qualitatively reproduce the overall cloud structure, the circulation around the cyclone is generally too weak. As a result, the model fails to represent the observed cloud to dynamics relationship. This wrong relationship in the model leads to a misrepresentation of the cloud field manifested as either an error in the cloud fraction or as simulating the "right" clouds for the "wrong" reason. The result underscores the importance of relationship-oriented model evaluation techniques over simple right or wrong assessments.

  10. Relationships

    ERIC Educational Resources Information Center

    Circle, David

    2006-01-01

    The author of this brief article asserts that one of the keys to being successful--whether one is a music teacher, a college professor, a business owner, a doctor, a lawyer, or in any other career--is his or her relationship with people. Music educators are in the people business. They do not make a tangible product. Instead, they provide a…

  11. Data Relationships: Towards a Conceptual Model of Scientific Data Catalogs

    NASA Astrophysics Data System (ADS)

    Hourcle, J. A.

    2008-12-01

    As the amount of data, types of processing and storage formats increase, the total number of record permutations increase dramatically. The result is an overwhelming number of records that make identifying the best data object to answer a user's needs more difficult. The issue is further complicated as each archive's data catalog may be designed around different concepts - - anything from individual files to be served, series of similarly generated and processed data, or something entirely different. Catalogs may not only be flat tables, but may be structured as multiple tables with each table being a different data series, or a normalized structure of the individual data files. Merging federated search results from archives with different catalog designs can create situations where the data object of interest is difficult to find due to an overwhelming number of seemingly similar or entirely unwanted records. We present a reference model for discussing data catalogs and the complex relationships between similar data objects. We show how the model can be used to improve scientist's ability to quickly identify the best data object for their purposes and discuss technical issues required to use this model in a federated system.

  12. Duration Models to Analyze Dating Relationship: The Controversial Role of Gift Giving.

    ERIC Educational Resources Information Center

    Huang, Ming-Hui; Yu, Shihti

    2000-01-01

    Econometric duration models were used to analyze dating relationships of 225 college students. Using gifts to enhance the self, express love, and announce relationships helped ensure the success of relationships. Gifts that were too frequent or rare resulted in self-depreciation and anxiety and harmed relationships. (SK)

  13. Structure-Activity Relationships in Toll-like Receptor-2 agonistic Diacylthioglycerol Lipopeptides

    PubMed Central

    Wu, Wenyan; Li, Rongti; Malladi, Subbalakshmi S.; Warshakoon, Hemamali J.; Kimbrell, Matthew R.; Amolins, Michael W.; Ukani, Rehman; Datta, Apurba; David, Sunil A.

    2010-01-01

    The N-termini of bacterial lipoproteins are acylated with a (S)-(2,3-bisacyloxypropyl)cysteinyl residue. Lipopeptides derived from lipoproteins activate innate immune responses by engaging Toll-like receptor 2 (TLR2), and are highly immunostimulatory and yet without apparent toxicity in animal models. The lipopeptides may therefore be useful as potential immunotherapeutic agents. Previous structure-activity relationships in such lipopeptides have largely been obtained using murine cells and it is now clear that significant species-specific differences exist between human and murine TLR responses. We have examined in detail the role of the highly conserved Cys residue as well as the geometry and stereochemistry of the Cys-Ser dipeptide unit. (R)-diacylthioglycerol analogues are maximally active in reporter gene assays using human TLR2. The Cys-Ser dipeptide unit represents the minimal part-structure, but its stereochemistry was found not to be a critical determinant of activity. The thioether bridge between the diacyl and dipeptide units is crucial, and replacement by an oxoether bridge results in a dramatic decrease in activity. PMID:20302301

  14. Further Studies on Structure-Cardiac Activity Relationships of Diterpenoid Alkaloids.

    PubMed

    Zhang, Zhong-Tang; Jian, Xi-Xian; Ding, Jia-Yu; Deng, Hong-Ying; Chao, Ruo-Bing; Chen, Qiao-Hong; Chen, Dong-Lin; Wang, Feng-Peng

    2015-12-01

    The cardiac effect of thirty-eight diterpenoid alkaloids was evaluated on the isolated bullfrog heart model. Among them, twelve compounds exhibited appreciable cardiac activity, with compounds 3 and 35 being more active than the reference drug lanatoside. The structure-cardiac activity relationships of the diterpenoid alkaloids were summarized based on our present and previous studies [2]: i) 1α-OMe or 1α-OH, 8-OH, 14-OH, and NH (or NMe) are key structural features important for the cardiac effect of the aconitine-type C19-diterpenoid alkaloids without any esters. C18-diterpenoid alkaloids, lycoctonine-type C19-diterpenoid alkaloids, and the veatchine- and denudatine-type C20-diterpenoid alkaloids did not show any cardiac activity; ii) the presence of 3α-OH is beneficial to the cardiac activity; iii) the effect on the cardiac action of 6α-OMe, 13-OH, 15α-OH, and 16-demethoxy or a double bond between C-15 and C-16 depends on the substituent pattern on the nitrogen atom.

  15. Synthesis and structure-activity relationship of trimebutine derivatives.

    PubMed

    Sai, H; Ozaki, Y; Hayashi, K; Onoda, Y; Yamada, K

    1996-06-01

    Trimebutine derivatives were synthesized by utilizing alkylation or acylation of isonitriles and nitrile as a key step. The colonic contractile effects of these compounds were examined, and T-1815 was found to have strong colonic propulsive activity. PMID:8814947

  16. An active region model for capturing fractal flow patterns in unsaturated soils: model development.

    PubMed

    Liu, H H; Zhang, R; Bodvarsson, G S

    2005-11-01

    Preferential flow commonly observed in unsaturated soils allows rapid movement of solute from the soil surface or vadose zone to the groundwater, bypassing a significant volume of unsaturated soil and increasing the risk of groundwater contamination. A variety of evidence indicates that complex preferential patterns observed from fields are fractals. In this study, we developed a relatively simple active region model to incorporate the fractal flow pattern into the continuum approach. In the model, the flow domain is divided into active and inactive regions. Flow occurs preferentially in the active region (characterized by fractals), and inactive region is simply bypassed. A new constitutive relationship (the portion of the active region as a function of saturation) was derived. The validity of the proposed model is demonstrated by the consistency between field observations and the new constitutive relationship.

  17. An Active Region Model for Capturing Fractal Flow Patterns inUnsaturated Soils: Model Development

    SciTech Connect

    Liu, Hui-Hai; Zhang, R.; Bodvarsson, Gudmundur S.

    2005-06-11

    Preferential flow commonly observed in unsaturated soils allows rapid movement of solute from the soil surface or vadose zone to the groundwater, bypassing a significant volume of unsaturated soil and increasing the risk of groundwater contamination. A variety of evidence indicates that complex preferential patterns observed from fields are fractals. In this study, we developed a relatively simple active region model to incorporate the fractal flow pattern into the continuum approach. In the model, the flow domain is divided into active and inactive regions. Flow occurs preferentially in the active region (characterized by fractals), and inactive region is simply bypassed. A new constitutive relationship (the portion of the active region as a function of saturation) was derived. The validity of the proposed model is demonstrated by the consistency between field observations and the new constitutive relationship.

  18. Using structural equation modeling to investigate relationships among ecological variables

    USGS Publications Warehouse

    Malaeb, Z.A.; Kevin, Summers J.; Pugesek, B.H.

    2000-01-01

    Structural equation modeling is an advanced multivariate statistical process with which a researcher can construct theoretical concepts, test their measurement reliability, hypothesize and test a theory about their relationships, take into account measurement errors, and consider both direct and indirect effects of variables on one another. Latent variables are theoretical concepts that unite phenomena under a single term, e.g., ecosystem health, environmental condition, and pollution (Bollen, 1989). Latent variables are not measured directly but can be expressed in terms of one or more directly measurable variables called indicators. For some researchers, defining, constructing, and examining the validity of latent variables may be the end task of itself. For others, testing hypothesized relationships of latent variables may be of interest. We analyzed the correlation matrix of eleven environmental variables from the U.S. Environmental Protection Agency's (USEPA) Environmental Monitoring and Assessment Program for Estuaries (EMAP-E) using methods of structural equation modeling. We hypothesized and tested a conceptual model to characterize the interdependencies between four latent variables-sediment contamination, natural variability, biodiversity, and growth potential. In particular, we were interested in measuring the direct, indirect, and total effects of sediment contamination and natural variability on biodiversity and growth potential. The model fit the data well and accounted for 81% of the variability in biodiversity and 69% of the variability in growth potential. It revealed a positive total effect of natural variability on growth potential that otherwise would have been judged negative had we not considered indirect effects. That is, natural variability had a negative direct effect on growth potential of magnitude -0.3251 and a positive indirect effect mediated through biodiversity of magnitude 0.4509, yielding a net positive total effect of 0

  19. Development and validation of a quantitative structure-activity relationship for chronic narcosis to fish.

    PubMed

    Claeys, Lieve; Iaccino, Federica; Janssen, Colin R; Van Sprang, Patrick; Verdonck, Frederik

    2013-10-01

    Vertebrate testing under the European Union's regulation on Registration, Evaluation, Authorisation and Restriction of Chemical substances (REACH) is discouraged, and the use of alternative nontesting approaches such as quantitative structure-activity relationships (QSARs) is encouraged. However, robust QSARs predicting chronic ecotoxicity of organic compounds to fish are not available. The Ecological Structure Activity Relationships (ECOSAR) Class Program is a computerized predictive system that estimates the acute and chronic toxicity of organic compounds for several chemical classes based on their log octanol-water partition coefficient (K(OW)). For those chemical classes for which chronic training data sets are lacking, acute to chronic ratios are used to predict chronic toxicity to aquatic organisms. Although ECOSAR reaches a high score against the Organisation for Economic Co-operation and Development (OECD) principles for QSAR validation, the chronic QSARs in ECOSAR are not fully compliant with OECD criteria in the framework of REACH or CLP (classification, labeling, and packaging) regulation. The objective of the present study was to develop a chronic ecotoxicity QSAR for fish for compounds acting via nonpolar and polar narcosis. These QSARs were built using a database of quality screened toxicity values, considering only chronic exposure durations and relevant end points. After statistical multivariate diagnostic analysis, literature-based, mechanistically relevant descriptors were selected to develop a multivariate regression model. Finally, these QSARs were tested for their acceptance for regulatory purposes and were found to be compliant with the OECD principles for the validation of a QSAR.

  20. Androgen receptor antagonists (antiandrogens): structure-activity relationships.

    PubMed

    Singh, S M; Gauthier, S; Labrie, F

    2000-02-01

    Prostate cancer, acne, seborrhea, hirsutism, and androgenic alopecia are well recognized to depend upon an excess or increased sensitivity to androgens or to be at least sensitive to androgens. It thus seems logical to use antiandrogens as therapeutic agents to prevent androgens from binding to the androgen receptor. The two predominant naturally occurring androgens are testosterone (T) and dihydrotestosterone (DHT). DHT is the more potent androgen in vivo and in vitro. All androgen-responsive genes are activated by androgen receptor (AR) bound to either T or DHT and it is believed that AR is more transcriptionally active when bound to DHT than T. The two classes of antiandrogens, presently available, are the steroidal derivatives, all of which possess mixed agonistic and antagonistic activities, and the pure non-steroidal antiandrogens of the class of flutamide and its derivatives. The intrinsic androgenic, estrogenic and glucocorticoid activities of steroidal derivatives have limited their use in the treatment of prostate cancer. The non-steroidal flutamide and its derivatives display pure antiandrogenic activity, without exerting agonistic or any other hormonal activity. Flutamide (89) and its derivatives, Casodex (108) and Anandron (114), are highly effective in the treatment of prostate cancer. The combination of flutamide and Anandron with castration has shown prolongation of life in prostate cancer. Furthermore, combined androgen blockade in association with radical prostatectomy or radiotherapy are very effective in the treatment of localized prostate cancer. Such an approach certainly raises the hope of a further improvement in prostate cancer therapy. However, all antiandrogens, developed so-far display moderate affinity for the androgen receptor, and thus moderate efficacy in vitro and in vivo. There is thus a need for next-generation antiandrogens, which could display an equal or even higher affinity for AR compared to the natural androgens, and at the

  1. Nutrient Models Developments Using Runoff-Nutrient Relationships in an Agricultural Prairie Basin, Manitoba.

    NASA Astrophysics Data System (ADS)

    Mahmood, T. H.; Pomeroy, J. W.; Wheater, H. S.; Elliott, J. A.; Baulch, H. M.; Lindenschmidt, K. E.

    2015-12-01

    Nutrient export to streams and lakes from agricultural activities can result in significant deterioration of water quality and aquatic ecosystem health. In Western Canada, particular concerns arise for prairie agricultural systems, which are dominated by the effects of a cold climate. Insufficient attention has been given to understand the links between cold region watershed responses and nutrient concentration and a robust watershed-scale modeling framework is needed to simulate nutrient concentration and loads. Long-term, field observations of nutrient concentration-runoff relationships were used to develop nutrient concentration models for the Tobacco Creek Model Watershed (TCMW) which drains into the Red River basin. Field observations include streamflow concentrations of N and P at multiple scales from two headwater basins. Distinct nutrient concentration-runoff models for snowmelt, rain on snow (ROS) and rainfall runoff processes were developed from observed runoff-nutrient concentration relationships. Snowmelt runoff had a moderately positive correlation with particulate nutrient concentrations but no correlation with that of dissolved nutrients. ROS runoff had a weak relationship with both particulate and dissolved nutrient concentrations. Rainfall runoff had the strongest positive correlation with particulate nutrient concentrations but no association with that of dissolved nutrients. The modeling approach also identified a clear hysteretic behavior in the relationship between runoff and particulate nutrient concentration during the 2013 snowmelt runoff event at the basin outlet gauge. The models provide insight into the hydrological controls on nutrient export from cold regions watersheds and the strong effects of inter-annual climatic variability. Snowmelt runoff is a reliable exporter of large nutrient loads while nutrient export by rainfall runoff exceeded snowmelt runoff during hydrologically wet summers such as 2002, 2005, 2011 and 2013.

  2. The relationship between active ghrelin levels and human obesity involves alterations in resting energy expenditure.

    PubMed

    Marzullo, Paolo; Verti, Barbara; Savia, Giulio; Walker, Gillian E; Guzzaloni, Gabriele; Tagliaferri, Mariantonella; Di Blasio, Annamaria; Liuzzi, Antonio

    2004-02-01

    Ghrelin is a gastric hormone that exerts a stimulatory effect on appetite and fat accumulation. Ser(3) octanoylation is regarded as a prerequisite for ghrelin biological activity, although des-octanoylated forms may retain biological functions in vitro. Circulating ghrelin levels are usually low in obesity and in states of positive energy balance. Hence, the aim of our study was to analyze plasma active and serum total ghrelin levels in 20 obese (ages, 22-42 yr; body mass index, 41.3 +/- 1.1 kg/m(2)) and 20 lean subjects (ages, 22-43 yr; body mass index, 22.4 +/- 0.6 kg/m(2)) as well as their relationship to measures of glucose homeostasis, body fat, and resting energy expenditure (REE). The measured/predicted REE percentage ratio was calculated to subdivide groups into those with positive (> or = 100% ) and negative (<100%) ratio values. In obese patients, plasma active (180 +/- 18 vs. 411 +/- 57 pg/ml; P < 0.001) and serum total ghrelin levels (3650 +/- 408 vs. 5263 +/- 643 pg/ml; P < 0.05) were significantly lower when compared with lean subjects. Hence, ghrelin activity, defined as the proportion of active over total ghrelin levels, was similarly reduced in the obese state (6.1 +/- 0.9% vs. 8.4 +/- 1%; P < 0.05). There was a significant correlation between active and total ghrelin (r = 0.62; P < 0.001), and between total ghrelin and insulin (r = -0.53; P < 0.001) or insulin resistance using the homeostatis model of assessment-insulin resistance (r = -0.49; P < 0.001) approach. Significantly higher active ghrelin levels (214 +/- 22 vs. 159 +/- 30 pg/ml; P < 0.05) and ghrelin activity (8 +/- 1.7% vs. 4.9 +/- 0.9%; P < 0.05) were observed in patients with positive compared with negative measured/predicted REE ratio values. Our study shows that obesity is associated with an impairment of the entire ghrelin system. The observation that ghrelin is further decreased in cases of abnormal energy profit adds new evidence to the relationship between ghrelin activity and

  3. Applying quantitative structure-activity relationship approaches to nanotoxicology: current status and future potential.

    PubMed

    Winkler, David A; Mombelli, Enrico; Pietroiusti, Antonio; Tran, Lang; Worth, Andrew; Fadeel, Bengt; McCall, Maxine J

    2013-11-01

    The potential (eco)toxicological hazard posed by engineered nanoparticles is a major scientific and societal concern since several industrial sectors (e.g. electronics, biomedicine, and cosmetics) are exploiting the innovative properties of nanostructures resulting in their large-scale production. Many consumer products contain nanomaterials and, given their complex life-cycle, it is essential to anticipate their (eco)toxicological properties in a fast and inexpensive way in order to mitigate adverse effects on human health and the environment. In this context, the application of the structure-toxicity paradigm to nanomaterials represents a promising approach. Indeed, according to this paradigm, it is possible to predict toxicological effects induced by chemicals on the basis of their structural similarity with chemicals for which toxicological endpoints have been previously measured. These structure-toxicity relationships can be quantitative or qualitative in nature and they can predict toxicological effects directly from the physicochemical properties of the entities (e.g. nanoparticles) of interest. Therefore, this approach can aid in prioritizing resources in toxicological investigations while reducing the ethical and monetary costs that are related to animal testing. The purpose of this review is to provide a summary of recent key advances in the field of QSAR modelling of nanomaterial toxicity, to identify the major gaps in research required to accelerate the use of quantitative structure-activity relationship (QSAR) methods, and to provide a roadmap for future research needed to achieve QSAR models useful for regulatory purposes. PMID:23165187

  4. Applying quantitative structure-activity relationship approaches to nanotoxicology: current status and future potential.

    PubMed

    Winkler, David A; Mombelli, Enrico; Pietroiusti, Antonio; Tran, Lang; Worth, Andrew; Fadeel, Bengt; McCall, Maxine J

    2013-11-01

    The potential (eco)toxicological hazard posed by engineered nanoparticles is a major scientific and societal concern since several industrial sectors (e.g. electronics, biomedicine, and cosmetics) are exploiting the innovative properties of nanostructures resulting in their large-scale production. Many consumer products contain nanomaterials and, given their complex life-cycle, it is essential to anticipate their (eco)toxicological properties in a fast and inexpensive way in order to mitigate adverse effects on human health and the environment. In this context, the application of the structure-toxicity paradigm to nanomaterials represents a promising approach. Indeed, according to this paradigm, it is possible to predict toxicological effects induced by chemicals on the basis of their structural similarity with chemicals for which toxicological endpoints have been previously measured. These structure-toxicity relationships can be quantitative or qualitative in nature and they can predict toxicological effects directly from the physicochemical properties of the entities (e.g. nanoparticles) of interest. Therefore, this approach can aid in prioritizing resources in toxicological investigations while reducing the ethical and monetary costs that are related to animal testing. The purpose of this review is to provide a summary of recent key advances in the field of QSAR modelling of nanomaterial toxicity, to identify the major gaps in research required to accelerate the use of quantitative structure-activity relationship (QSAR) methods, and to provide a roadmap for future research needed to achieve QSAR models useful for regulatory purposes.

  5. A Rapid Approach to Modeling Species-Habitat Relationships

    NASA Technical Reports Server (NTRS)

    Carter, Geoffrey M.; Breinger, David R.; Stolen, Eric D.

    2005-01-01

    A growing number of species require conservation or management efforts. Success of these activities requires knowledge of the species' occurrence pattern. Species-habitat models developed from GIS data sources are commonly used to predict species occurrence but commonly used data sources are often developed for purposes other than predicting species occurrence and are of inappropriate scale and the techniques used to extract predictor variables are often time consuming and cannot be repeated easily and thus cannot efficiently reflect changing conditions. We used digital orthophotographs and a grid cell classification scheme to develop an efficient technique to extract predictor variables. We combined our classification scheme with a priori hypothesis development using expert knowledge and a previously published habitat suitability index and used an objective model selection procedure to choose candidate models. We were able to classify a large area (57,000 ha) in a fraction of the time that would be required to map vegetation and were able to test models at varying scales using a windowing process. Interpretation of the selected models confirmed existing knowledge of factors important to Florida scrub-jay habitat occupancy. The potential uses and advantages of using a grid cell classification scheme in conjunction with expert knowledge or an habitat suitability index (HSI) and an objective model selection procedure are discussed.

  6. Initial insights into structure-activity relationships of avian defensins.

    PubMed

    Derache, Chrystelle; Meudal, Hervé; Aucagne, Vincent; Mark, Kevin J; Cadène, Martine; Delmas, Agnès F; Lalmanach, Anne-Christine; Landon, Céline

    2012-03-01

    Numerous β-defensins have been identified in birds, and the potential use of these peptides as alternatives to antibiotics has been proposed, in particular to fight antibiotic-resistant and zoonotic bacterial species. Little is known about the mechanism of antibacterial activity of avian β-defensins, and this study was carried out to obtain initial insights into the involvement of structural features or specific residues in the antimicrobial activity of chicken AvBD2. Chicken AvBD2 and its enantiomeric counterpart were chemically synthesized. Peptide elongation and oxidative folding were both optimized. The similar antimicrobial activity measured for both L- and D-proteins clearly indicates that there is no chiral partner. Therefore, the bacterial membrane is in all likelihood the primary target. Moreover, this work indicates that the three-dimensional fold is required for an optimal antimicrobial activity, in particular for gram-positive bacterial strains. The three-dimensional NMR structure of chicken AvBD2 defensin displays the structural three-stranded antiparallel β-sheet characteristic of β-defensins. The surface of the molecule does not display any amphipathic character. In light of this new structure and of the king penguin AvBD103b defensin structure, the consensus sequence of the avian β-defensin family was analyzed. Well conserved residues were highlighted, and the potential strategic role of the lysine 31 residue of AvBD2 was emphasized. The synthetic AvBD2-K31A variant displayed substantial N-terminal structural modifications and a dramatic decrease in activity. Taken together, these results demonstrate the structural as well as the functional role of the critical lysine 31 residue in antimicrobial activity. PMID:22205704

  7. A Commentary on the Relationship between Model Fit and Saturated Path Models in Structural Equation Modeling Applications

    ERIC Educational Resources Information Center

    Raykov, Tenko; Lee, Chun-Lung; Marcoulides, George A.; Chang, Chi

    2013-01-01

    The relationship between saturated path-analysis models and their fit to data is revisited. It is demonstrated that a saturated model need not fit perfectly or even well a given data set when fit to the raw data is examined, a criterion currently frequently overlooked by researchers utilizing path analysis modeling techniques. The potential of…

  8. Toward a Life Span Theory of Close Relationships: The Affective Relationships Model

    ERIC Educational Resources Information Center

    Takahashi, Keiko

    2005-01-01

    This article addresses how close relationships can be conceptualized so that they can be accurately understood over the life span. First, two typical clusters of theories of close relationships, the attachment theory and the social network theory, are compared and discussed with regard to their fundamental but controversial assumptions regarding…

  9. Activities and Accomplishments in Various Domains: Relationships with Creative Personality and Creative Motivation in Adolescence

    ERIC Educational Resources Information Center

    Hong, Eunsook; Peng, Yun; O'Neil, Harold F., Jr.

    2014-01-01

    This study examined relationships between five personal traits and adolescents' creative activities and accomplishments in five domains--music, visual arts, creative writing, science, and technology. Participants were 439 tenth graders (220 males and 219 females) in China. The relationships were examined using confirmatory factor analysis.…

  10. Adolescents Online: The Importance of Internet Activity Choices to Salient Relationships

    ERIC Educational Resources Information Center

    Blais, Julie J.; Craig, Wendy M.; Pepler, Debra; Connolly, Jennifer

    2008-01-01

    The purpose of this study was to determine whether using the Internet for different activities affects the quality of close adolescent relationships (i.e., best friendships and romantic relationships). In a one-year longitudinal study of 884 adolescents (Mean age = 15, 46% male), we examined whether visiting chat rooms, using ICQ, using the…

  11. The Relationship between Cortisol Activity during Cognitive Task and Posttraumatic Stress Symptom Clusters

    PubMed Central

    Duan, Hongxia; Wang, Li; Zhang, Liang; Liu, Jing; Zhang, Kan; Wu, Jianhui

    2015-01-01

    Background The latest development in the dimensional structure of posttraumatic stress disorder (PTSD) is a novel 6-factor model, which builds on the newly released DSM-5. One notable gap in the literature is that little is known about how distinct symptom clusters of PTSD are related to hypothalamic–pituitary–adrenal (HPA) axis activity when people perform a relatively less stressful cognitive task. The purpose of this study was to investigate the relationship between cortisol activity when individuals perform cognitive tasks in the laboratory and a contemporary phenotypic model of posttraumatic stress symptomatology in earthquake survivors. Methods Salivary cortisol while performing cognitive tasks was collected and analyzed in 89 adult earthquake survivors. The PTSD Checklist for the DSM-5 (PCL-5) was used to assess the severity of total PTSD as well as six distinct symptom clusters. Regression analyses were conducted to examine the associations between the six distinct PTSD symptom clusters and cortisol profiles. Results The results showed that the score of the negative affect symptom cluster, but not anhedonia or other clusters, was positively associated with cortisol levels before and during the cognitive tasks. Conclusion The results showed that higher cortisol levels before and during cognitive tasks might be specifically linked to a distinct symptom cluster of PTSD—negative affect symptomatology. This suggests that a distinction should be made between negative affect and anhedonia symptom clusters, as the 6-factor model proposed. PMID:26630485

  12. Habit as moderator of the intention-physical activity relationship in older adults: a longitudinal study.

    PubMed

    van Bree, Rob J H; van Stralen, Maartje M; Bolman, Catherine; Mudde, Aart N; de Vries, Hein; Lechner, Lilian

    2013-01-01

    This longitudinal study examined whether habit strength moderates the intention-physical activity (PA) relationship in older adults, within the framework of the attitude-social influences-efficacy (ASE) model and the theory of planned behaviour (TPB). A total of 1836 older adults (Mage = 62.95 years, SDage = 8.17) completed a questionnaire on social cognitive constructs and PA habit strength at baseline, and six months later a measure of PA. Three PA habit groups (i.e., low, medium and high) were composed, based on tertiles of the mean index score. Multi-group structural equation modelling analyses showed that intention significantly determined PA behaviour only in participants with a low or medium habit strength towards PA. This result suggests that PA is not intentional at high levels of habit strength and demonstrates the usefulness of incorporating habit in the ASE and TPB models. Results also showed that about half of the participants with a strong PA habit did not meet the recommended PA level. As strong habits may prevent intentional behavioural change and may hinder the receptiveness and openness for informational PA change strategies, additional intervention strategies, such as awareness raising and the use of implementation intentions, are needed for strongly habitual, but insufficiently active older adults. PMID:23244776

  13. Does Physical Activity Intensity Moderate Social Cognition and Behavior Relationships?

    ERIC Educational Resources Information Center

    Scott, Felicity; Rhodes, Ryan E.; Downs, Danielle Symons

    2009-01-01

    Objective: Public health messaging about physical activity (PA) sometimes combines moderate and vigorous intensity, but the variance/invariance of the motives for PA by intensity has received scant attention. Thus, the purpose of this study was to examine the beliefs and motivations associated with regular moderate- and vigorous-intensity PA in a…

  14. Instructional Transaction Theory: Knowledge Relationships among Processes, Entities, and Activities.

    ERIC Educational Resources Information Center

    Merrill, M. David; And Others

    1993-01-01

    Discussion of instructional transaction theory focuses on knowledge representation in an automated instructional design expert system. A knowledge structure called PEA-Net (processes, entities, and activities) is explained; the refrigeration process is used as an example; text resources and graphic resources are described; and simulations are…

  15. Prospective relationships of physical activity with quality of life among colorectal cancer survivors

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Physical activity can enhance quality of life for cancer survivors. However, few longitudinal studies have examined whether physical activity has a sustained effect on improvements in quality of life. The present study aims to examine the relationships between physical activity and quality of life o...

  16. Brief Report: Relationships between Physical Activity and Depressive Symptoms in Adolescent Girls

    ERIC Educational Resources Information Center

    Raudsepp, Lennart; Neissaar, Inga

    2012-01-01

    This study examined the relationships between changes in physical activity and depressive symptoms in adolescent girls. Participants were 277 urban adolescent girls. Physical activity was measured using the 3-Day Physical Activity Recall and depressive symptoms were assessed using questionnaire. Data were collected on three occasions over a 3-year…

  17. The Relationship between Aerobic Capacity and Physical Activity in Blind and Sighted Adolescents.

    ERIC Educational Resources Information Center

    Kobberling, G.; And Others

    1991-01-01

    This study investigated the relationship between habitual physical activity and aerobic capacity in 30 blind and 30 sighted adolescents. Both physical activity and maximal oxygen consumption were significantly higher among the sighted adolescents. A minimum of 30 minutes of daily activity at a minimal oxygen consumption of 8 METs (resting…

  18. Relationships Between Vocal Activity and Perception of Communicators in Small Group Interaction

    ERIC Educational Resources Information Center

    Daley, John A.; And Others

    1977-01-01

    Discusses a study designed to investigate the relationships between vocal activity level and interpersonal attraction, perceived credibility, perceived homophily or interpersonal similarity and perceived power or ability to influence. (MH)

  19. MOLECULAR INTERACTION POTENTIALS FOR THE DEVELOPMENT OF STRUCTURE-ACTIVITY RELATIONSHIPS

    EPA Science Inventory

    Abstract
    One reasonable approach to the analysis of the relationships between molecular structure and toxic activity is through the investigation of the forces and intermolecular interactions responsible for chemical toxicity. The interaction between the xenobiotic and the bio...

  20. PREDICTING TOXICOLOGICAL ENDPOINTS OF CHEMICALS USING QUANTITATIVE STRUCTURE-ACTIVITY RELATIONSHIPS (QSARS)

    EPA Science Inventory

    Quantitative structure-activity relationships (QSARs) are being developed to predict the toxicological endpoints for untested chemicals similar in structure to chemicals that have known experimental toxicological data. Based on a very large number of predetermined descriptors, a...

  1. Hologram quantitative structure activity relationship, docking, and molecular dynamics studies of inhibitors for CXCR4.

    PubMed

    Zhang, Chongqian; Du, Chunmiao; Feng, Zhiwei; Zhu, Jingyu; Li, Youyong

    2015-02-01

    CXCR4 plays a crucial role as a co-receptor with CCR5 for HIV-1 anchoring to mammalian cell membrane and is implicated in cancer metastasis and inflammation. In the current work, we study the relationship of structure and activity of AMD11070 derivatives and other inhibitors of CXCR4 using HQSAR, docking and molecular dynamics (MD) simulations. We obtain an HQSAR model (q(2) = 0.779), and the HQSAR result illustrates that AMD11070 shows a high antiretroviral activity. As HQSAR only provides 2D information, we perform docking and MD to study the interaction of It1t, AMD3100, and AMD3465 with CXCR4. Our results illustrate that the binding are affected by two crucial residues Asp97 and Glu288. The butyl amine moiety of AMD11070 contributes to its high antiretroviral activity. Without a butyl amine moiety, (2,7a-Dihydro-1H-benzoimidazol-2-ylmethyl)-methyl-(5,6,7,8-tetrahydro-quinolin-8-yl)-amine (compound 5a) shows low antiretroviral activity. Our results provide structural details about the interactions between the inhibitors and CXCR4, which are useful for rational drug design of CXCR4.

  2. Relationship of gonadal activity and chemotherapy-induced gonadal damage

    SciTech Connect

    Rivkees, S.A.; Crawford, J.D.

    1988-04-08

    The authors tested the hypothesis that chemotherapy-induced gonadal damage is proportional to the degree of gonadal activity during treatment. Thirty studies that evaluated gonadal function after cyclophosphamide therapy for renal disease or combination chemotherapy for Hodgkin's disease or acute lymphocytic leukemia provided data for analysis. Data were stratified according to sex, illness, chemotherapeutic regimen and dose, and pubertal stage at the time of treatment. Chemotherapy-induced damage was more likely to occur in patients who were treated when sexually mature compared with those who were treated when prepubertal. Males were significantly more frequently affected than females when treated for renal disease of Hodgkin's disease. Chemotherapy-induced damage was also more likely to occur when patients were treated with large doses of alkylating agents. These data suggest that chemotherapy-induced damage is proportional to gonadal activity. Further efforts are needed to test whether induced gonadal quiescence during chemotherapy will reduce the strikingly high incidence of gonadal failure following chemotherapy.

  3. Time-activity relationships to VOC personal exposure factors

    NASA Astrophysics Data System (ADS)

    Edwards, Rufus D.; Schweizer, Christian; Llacqua, Vito; Lai, Hak Kan; Jantunen, Matti; Bayer-Oglesby, Lucy; Künzli, Nino

    Social and demographic factors have been found to play a significant role in differences between time-activity patterns of population subgroups. Since time-activity patterns largely influence personal exposure to compounds as individuals move across microenvironments, exposure subgroups within the population may be defined by factors that influence daily activity patterns. Socio-demographic and environmental factors that define time-activity subgroups also define quantifiable differences in VOC personal exposures to different sources and individual compounds in the Expolis study. Significant differences in exposures to traffic-related compounds ethylbenzene, m- and p-xylene and o-xylene were observed in relation to gender, number of children and living alone. Categorization of exposures further indicated time exposed to traffic at work and time in a car as important determinants. Increased exposures to decane, nonane and undecane were observed for males, housewives and self-employed. Categorization of exposures indicated exposure subgroups related to workshop use and living downtown. Higher exposures to 3-carene and α-pinene commonly found in household cleaning products and fragrances were associated with more children, while exposures to traffic compounds ethylbenzene, m- and p-xylene and o-xylene were reduced with more children. Considerable unexplained variation remained in categorization of exposures associated with home product use and fragrances, due to individual behavior and product choice. More targeted data collection methods in VOC exposure studies for these sources should be used. Living alone was associated with decreased exposures to 2-methyl-1-propanol and 1-butanol, and traffic-related compounds. Identification of these subgroups may help to reduce the large amount of unexplained variation in VOC exposure studies. Further they may help in assessing impacts of urban planning that result in changes in behavior of individuals, resulting in shifts in

  4. Structure-Activity Relationship of Chlorotoxin-Like Peptides

    PubMed Central

    Ali, Syed Abid; Alam, Mehtab; Abbasi, Atiya; Undheim, Eivind A. B.; Fry, Bryan Grieg; Kalbacher, Hubert; Voelter, Wolfgang

    2016-01-01

    Animal venom (e.g., scorpion) is a rich source of various protein and peptide toxins with diverse physio-/pharmaco-logical activities, which generally exert their action via target-specific modulation of different ion channel functions. Scorpion venoms are among the most widely-known source of peptidyl neurotoxins used for callipering different ion channels, such as; Na+, K+, Ca+, Cl−, etc. A new peptide of the chlorotoxin family (i.e., Bs-Tx7) has been isolated, sequenced and synthesized from scorpion Buthus sindicus (family Buthidae) venom. This peptide demonstrates 66% with chlorotoxin (ClTx) and 82% with CFTR channel inhibitor (GaTx1) sequence identities reported from Leiurus quinquestriatus hebraeus venom. The toxin has a molecular mass of 3821 Da and possesses four intra-chain disulphide bonds. Amino acid sequence analysis of Bs-Tx7 revealed the presence of a scissile peptide bond (i.e., Gly-Ile) for human MMP2, whose activity is increased in the case of tumour malignancy. The effect of hMMP2 on Bs-Tx7, or vice versa, observed using the FRET peptide substrate with methoxycoumarin (Mca)/dinitrophenyl (Dnp) as fluorophore/quencher, designed and synthesized to obtain the lowest Km value for this substrate, showed approximately a 60% increase in the activity of hMMP2 upon incubation of Bs-Tx7 with the enzyme at a micromolar concentration (4 µM), indicating the importance of this toxin in diseases associated with decreased MMP2 activity. PMID:26848686

  5. Structure-Activity Relationship of Chlorotoxin-Like Peptides.

    PubMed

    Ali, Syed Abid; Alam, Mehtab; Abbasi, Atiya; Undheim, Eivind A B; Fry, Bryan Grieg; Kalbacher, Hubert; Voelter, Wolfgang

    2016-02-02

    Animal venom (e.g., scorpion) is a rich source of various protein and peptide toxins with diverse physio-/pharmaco-logical activities, which generally exert their action via target-specific modulation of different ion channel functions. Scorpion venoms are among the most widely-known source of peptidyl neurotoxins used for callipering different ion channels, such as; Na⁺, K⁺, Ca⁺, Cl(-), etc. A new peptide of the chlorotoxin family (i.e., Bs-Tx7) has been isolated, sequenced and synthesized from scorpion Buthus sindicus (family Buthidae) venom. This peptide demonstrates 66% with chlorotoxin (ClTx) and 82% with CFTR channel inhibitor (GaTx1) sequence identities reported from Leiurus quinquestriatus hebraeus venom. The toxin has a molecular mass of 3821 Da and possesses four intra-chain disulphide bonds. Amino acid sequence analysis of Bs-Tx7 revealed the presence of a scissile peptide bond (i.e., Gly-Ile) for human MMP2, whose activity is increased in the case of tumour malignancy. The effect of hMMP2 on Bs-Tx7, or vice versa, observed using the FRET peptide substrate with methoxycoumarin (Mca)/dinitrophenyl (Dnp) as fluorophore/quencher, designed and synthesized to obtain the lowest Km value for this substrate, showed approximately a 60% increase in the activity of hMMP2 upon incubation of Bs-Tx7 with the enzyme at a micromolar concentration (4 µM), indicating the importance of this toxin in diseases associated with decreased MMP2 activity.

  6. Structure-activity relationship of buffalo antibacterial hepcidin analogs.

    PubMed

    Chanu, Khangembam Victoria; Kumar, Ashok; Kumar, Satish

    2011-10-01

    Hepcidin is an anti-microbial peptide expressed predominantly in the liver of many species. Based on the amino acid sequence deduced from buffalo (Bubalus bubalis) hepcidin cDNA (Accession no. EU399814), six peptides Hepc(1-25), Hepc(6-25), Hepc(7-25), Hepc(9-25), Hepc(11-25) and Hepc(15-25) were synthesized using solid-phase fluorenylmethoxycarbonyl (Fmoc) chemistry. CD spectroscopy revealed different spectra of the peptides in different solvents and in all the cases beta-structure was found to be dominant with less alpha-helix as predicted. Quantitation of secondary structure indicated the highest beta-structure for all the six peptides in SDS solution, when used as mimetic for membrane-like environment. The CD spectra of all the peptides taken in water showed that degree of randomness decreased with increase in chain length of the peptide. Out of the six peptides, only Hepc(1-25), Hepc(6-25) and Hepc(7-25) showed antibacterial activity against Staphylococcus aureus (Gram-positive bacteria). The peptides did not show any sensitivity toward E. coli (Gram-negative bacteria). Minimum inhibitory concentration (MIC) showed the lowest value for Hepc(7-25) as an antibacterial agent, followed by Hepc(6-25) and Hepc(1-25). The peptides Hepc(9-25), Hepc(11-25) and Hepc(15-25) with more random structure did not show any antimicrobial activity The study demonstrated that 5 amino acids at N-terminal in buffalo hepcidin can be truncated without loss of antimicrobial activity and further reduction of length of the analog from 20 to 19 amino acids resulted increase in the activity because of increase in beta-structure of the peptide shown by CD spectroscopy.

  7. Entrepreneurship education: relationship between education and entrepreneurial activity.

    PubMed

    Raposo, Mário; do Paço, Arminda

    2011-08-01

    The importance of entrepreneurial activity for the economic growth of countries is now well established. The relevant literature suggests important links between education, venture creation and entrepreneurial performance, as well as between entrepreneurial education and entrepreneurial activity. The primary purpose of this paper is to provide some insights about entrepreneurship education. The meaning of entrepreneurship education is explained, and the significant increase of these educational programmes is highlighted. Literature has been suggesting that the most suitable indicator to evaluate the results of entrepreneurship education is the rate of new business creation. However, some studies indicate that the results of such programmes are not immediate. Therefore, many researchers try to understand the precursors of venture creation, concluding that is necessary to carry out longitudinal studies. Based on an overview of the research published about the existing linkage of entrepreneurship education and entrepreneurial activity, the main topics studied by different academics are addressed. For the authors, the positive impact of entrepreneurship education puts a double challenge on governments in the future: the increased need of financial funds to support entrepreneurship education and the choice of the correct educational programme.

  8. Muscular activity and its relationship to biomechanics and human performance

    NASA Technical Reports Server (NTRS)

    Ariel, Gideon

    1994-01-01

    The purpose of this manuscript is to address the issue of muscular activity, human motion, fitness, and exercise. Human activity is reviewed from the historical perspective as well as from the basics of muscular contraction, nervous system controls, mechanics, and biomechanical considerations. In addition, attention has been given to some of the principles involved in developing muscular adaptations through strength development. Brief descriptions and findings from a few studies are included. These experiments were conducted in order to investigate muscular adaptation to various exercise regimens. Different theories of strength development were studied and correlated to daily human movements. All measurement tools used represent state of the art exercise equipment and movement analysis. The information presented here is only a small attempt to understand the effects of exercise and conditioning on Earth with the objective of leading to greater knowledge concerning human responses during spaceflight. What makes life from nonliving objects is movement which is generated and controlled by biochemical substances. In mammals. the controlled activators are skeletal muscles and this muscular action is an integral process composed of mechanical, chemical, and neurological processes resulting in voluntary and involuntary motions. The scope of this discussion is limited to voluntary motion.

  9. Linear Equating for the NEAT Design: Parameter Substitution Models and Chained Linear Relationship Models

    ERIC Educational Resources Information Center

    Kane, Michael T.; Mroch, Andrew A.; Suh, Youngsuk; Ripkey, Douglas R.

    2009-01-01

    This paper analyzes five linear equating models for the "nonequivalent groups with anchor test" (NEAT) design with internal anchors (i.e., the anchor test is part of the full test). The analysis employs a two-dimensional framework. The first dimension contrasts two general approaches to developing the equating relationship. Under a "parameter…

  10. Mental Models and Creative Problem-Solving: The Relationship of Objective and Subjective Model Attributes

    ERIC Educational Resources Information Center

    Mumford, Michael D.; Hester, Kimberly S.; Robledo, Issac C.; Peterson, David R.; Day, Eric A.; Hougen, Dean F.; Barrett, Jamie D.

    2012-01-01

    Knowledge, or expertise, has been held to contribute to creative problem-solving. In this effort, the relationship of one form of knowledge, mental models, to creative problem-solving was assessed. Undergraduates were asked to solve either a marketing or an education problem calling for creative thought. Prior to generating solutions to these…

  11. A quantitative structure-activity relationship to predict efficacy of granular activated carbon adsorption to control emerging contaminants.

    PubMed

    Kennicutt, A R; Morkowchuk, L; Krein, M; Breneman, C M; Kilduff, J E

    2016-08-01

    A quantitative structure-activity relationship was developed to predict the efficacy of carbon adsorption as a control technology for endocrine-disrupting compounds, pharmaceuticals, and components of personal care products, as a tool for water quality professionals to protect public health. Here, we expand previous work to investigate a broad spectrum of molecular descriptors including subdivided surface areas, adjacency and distance matrix descriptors, electrostatic partial charges, potential energy descriptors, conformation-dependent charge descriptors, and Transferable Atom Equivalent (TAE) descriptors that characterize the regional electronic properties of molecules. We compare the efficacy of linear (Partial Least Squares) and non-linear (Support Vector Machine) machine learning methods to describe a broad chemical space and produce a user-friendly model. We employ cross-validation, y-scrambling, and external validation for quality control. The recommended Support Vector Machine model trained on 95 compounds having 23 descriptors offered a good balance between good performance statistics, low error, and low probability of over-fitting while describing a wide range of chemical features. The cross-validated model using a log-uptake (qe) response calculated at an aqueous equilibrium concentration (Ce) of 1 μM described the training dataset with an r(2) of 0.932, had a cross-validated r(2) of 0.833, and an average residual of 0.14 log units. PMID:27586364

  12. A quantitative structure-activity relationship to predict efficacy of granular activated carbon adsorption to control emerging contaminants.

    PubMed

    Kennicutt, A R; Morkowchuk, L; Krein, M; Breneman, C M; Kilduff, J E

    2016-08-01

    A quantitative structure-activity relationship was developed to predict the efficacy of carbon adsorption as a control technology for endocrine-disrupting compounds, pharmaceuticals, and components of personal care products, as a tool for water quality professionals to protect public health. Here, we expand previous work to investigate a broad spectrum of molecular descriptors including subdivided surface areas, adjacency and distance matrix descriptors, electrostatic partial charges, potential energy descriptors, conformation-dependent charge descriptors, and Transferable Atom Equivalent (TAE) descriptors that characterize the regional electronic properties of molecules. We compare the efficacy of linear (Partial Least Squares) and non-linear (Support Vector Machine) machine learning methods to describe a broad chemical space and produce a user-friendly model. We employ cross-validation, y-scrambling, and external validation for quality control. The recommended Support Vector Machine model trained on 95 compounds having 23 descriptors offered a good balance between good performance statistics, low error, and low probability of over-fitting while describing a wide range of chemical features. The cross-validated model using a log-uptake (qe) response calculated at an aqueous equilibrium concentration (Ce) of 1 μM described the training dataset with an r(2) of 0.932, had a cross-validated r(2) of 0.833, and an average residual of 0.14 log units.

  13. Blood-brain barrier permeability mechanisms in view of quantitative structure-activity relationships (QSAR).

    PubMed

    Bujak, Renata; Struck-Lewicka, Wiktoria; Kaliszan, Michał; Kaliszan, Roman; Markuszewski, Michał J

    2015-04-10

    The goal of the present paper was to develop a quantitative structure-activity relationship (QSAR) method using a simple statistical approach, such as multiple linear regression (MLR) for predicting the blood-brain barrier (BBB) permeability of chemical compounds. The "best" MLR models, comprised logP and either molecular mass (M) or isolated atomic energy (E(isol)), tested on a structurally diverse set of 66 compounds, is characterized the by correlation coefficients (R) around 0.8. The obtained models were validated using leave-one-out (LOO) cross-validation technique and the correlation coefficient of leave-one-out- R(LOO)(2) (Q(2)) was at least 0.6. Analysis of a case from legal medicine demonstrated informative value of our QSAR model. To best authors' knowledge the present study is a first application of the developed QSAR models of BBB permeability to case from the legal medicine. Our data indicate that molecular energy-related descriptors, in combination with the well-known descriptors of lipophilicity may have a supportive value in predicting blood-brain distribution, which is of utmost importance in drug development and toxicological studies.

  14. Immunomodulatory assays to study structure-activity relationships of thalidomide.

    PubMed

    Shannon, E J; Morales, M J; Sandoval, F

    1997-01-01

    Thalidomide, which has a long history of tragedy because of its ability to cause severe birth defects, is very effective in alleviating erythema nodosum leprosum in leprosy patients and aphthous ulcers in AIDS patients. The causes of these inflammatory diseases and the mechanism by which thalidomide diminishes them are unknown. It has been suggested that modulation of the immune response plays an important role. We found that thalidomide exerts immunomodulatory activity in three bioassays. It suppresses an IgM plaque forming cell response in mice injected with sheep erythrocytes: it inhibits TNF-alpha production by LPS stimulated human mononuclear cells: and it enhances IL-2 production by Con-A stimulated human mononuclear cells. We employed these bioassays to compare the activity of 15 analogs of thalidomide with thalidomide itself. Eight of the compounds were derivatives of the glutarimide moiety of thalidomide and the others were phthalimide or derivatives of the phthalimide moiety of thalidomide. N-hydroxyphthalimide, a simple derivative of phthalimide, was more effective than thalidomide and was also the most effective of the compounds assayed in suppressing the IgM plaque and TNF-alpha responses, but it did not enhance the IL-2 response, instead, it significantly suppressed it.

  15. Relationship between the latest activity of mare volcanism and topographic features of the Moon

    NASA Astrophysics Data System (ADS)

    Kato, Shinsuke; Morota, Tomokatsu; Yamaguchi, Yasushi; Watanabe, Sei-ichiro; Otake, Hisashi; Ohtake, Makiko

    2016-04-01

    Lunar mare basalts provide insights into compositions and thermal history of lunar mantle. According to crater counting analysis with remote sensing data, the model ages of mare basalt units indicate a second peak of magma activity at the end of mare volcanism (~2 Ga), and the latest eruptions were limited in the Procellarum KREEP Terrane (PKT), which has high abundances of heat-producing elements. In order to understand the mechanism for causing the second peak and its magma source, we examined the correlation between the titanium contents and eruption ages of mare basalt units using compositional and chronological data updated by SELENE/Kaguya. Although no systematic relationship is observed globally, a rapid increase in mean titanium (Ti) content occurred at 2.3 Ga in the PKT, suggesting that the magma source of mare basalts changed at that time. The high-Ti basaltic eruption, which occurred at the late stage of mare volcanism, can be correlated with the second peak of volcanic activity at ~2 Ga. The latest volcanic activity can be explained by a high-Ti hot plume originated from the core-mantle boundary. If the hot plume was occurred, the topographic features formed by the hot plume may be remained. We calculated the difference between topography and selenoid and found the circular feature like a plateau in the center of the PKT, which scale is ~1000 km horizontal and ~500 m vertical. We investigated the timing of ridge formation in the PKT by using stratigraphic relationship between mare basalts and ridges. The ridges were formed before and after the high-Ti basaltic eruptions and seem to be along with the plateau. These results suggest that the plateau formation is connected with the high-Ti basaltic eruptions.

  16. Localized heuristic inverse quantitative structure activity relationship with bulk descriptors using numerical gradients.

    PubMed

    Stålring, Jonna; Almeida, Pedro R; Carlsson, Lars; Helgee Ahlberg, Ernst; Hasselgren, Catrin; Boyer, Scott

    2013-08-26

    State-of-the-art quantitative structure-activity relationship (QSAR) models are often based on nonlinear machine learning algorithms, which are difficult to interpret. From a pharmaceutical perspective, QSARs are used to enhance the chemical design process. Ultimately, they should not only provide a prediction but also contribute to a mechanistic understanding and guide modifications to the chemical structure, promoting compounds with desirable biological activity profiles. Global ranking of descriptor importance and inverse QSAR have been used for these purposes. This paper introduces localized heuristic inverse QSAR, which provides an assessment of the relative ability of the descriptors to influence the biological response in an area localized around the predicted compound. The method is based on numerical gradients with parameters optimized using data sets sampled from analytical functions. The heuristic character of the method reduces the computational requirements and makes it applicable not only to fragment based methods but also to QSARs based on bulk descriptors. The application of the method is illustrated on congeneric QSAR data sets, and it is shown that the predicted influential descriptors can be used to guide structural modifications that affect the biological response in the desired direction. The method is implemented into the AZOrange Open Source QSAR package. The current implementation of localized heuristic inverse QSAR is a step toward a generally applicable method for elucidating the structure activity relationship specifically for a congeneric region of chemical space when using QSARs based on bulk properties. Consequently, this method could contribute to accelerating the chemical design process in pharmaceutical projects, as well as provide information that could enhance the mechanistic understanding for individual scaffolds.

  17. Activity composition relationships in silicate melts. Final report

    SciTech Connect

    Glazner, A.F.

    1990-12-31

    Equipment progress include furnace construction and electron microprobe installation. The following studies are underway: phase equilibria along basalt-rhyolite mixing line (olivine crystallization from natural silicic andensites, distribution of Fe and Mg between olivine and liquid, dist. of Ca and Na between plagioclase and liquid), enthalpy-composition relations in magmas (bulk heat capacity of alkali basalt), density model for magma ascent and contamination, thermobarometry in igneous systems (olivine/plagioclase phenocryst growth in Quat. basalt), high-pressure phase equilibria of alkali basalt, basalt-quartz mixing experiments, phase equilibria of East African basalts, and granitic minerals in mafic magma. (DLC)

  18. Styles in Intimate Relationships: The A-R-C Model.

    ERIC Educational Resources Information Center

    L'Abate, Luciano

    1983-01-01

    Links internal personality differentiation to external patterns of interpersonal style. Suggests three basic styles in intimate relationships: apathy, reactivity, and conductivity. Discusses each style in detail. (RC)

  19. Modeling the impact of spatial relationships on horizontal curve safety.

    PubMed

    Findley, Daniel J; Hummer, Joseph E; Rasdorf, William; Zegeer, Charles V; Fowler, Tyler J

    2012-03-01

    The curved segments of roadways are more hazardous because of the additional centripetalforces exerted on a vehicle, driver expectations, and other factors. The safety of a curve is dependent on various factors, most notably by geometric factors, but the location of a curve in relation to other curves is also thought to influence the safety of those curves because of a driver's expectation to encounter additional curves. The link between an individual curve's geometric characteristics and its safety performance has been established, but spatial considerations are typically not included in a safety analysis. The spatial considerations included in this research consisted of four components: distance to adjacent curves, direction of turn of the adjacent curves, and radius and length of the adjacent curves. The primary objective of this paper is to quantify the spatial relationship between adjacent horizontal curves and horizontal curve safety using a crash modification factor. Doing so enables a safety professional to more accurately estimate safety to allocate funding to reduce or prevent future collisions and more efficiently design new roadway sections to minimize crash risk where there will be a series of curves along a route. The most important finding from this research is the statistical significance of spatial considerations for the prediction of horizontal curve safety. The distances to adjacent curves were found to be a reliable predictor of observed collisions. This research recommends a model which utilizes spatial considerations for horizontal curve safety prediction in addition to current Highway Safety Manual prediction capabilities using individual curve geometric features.

  20. Bradykinin actively modulates pulmonary vascular pressure-cardiac index relationships.

    PubMed

    Nyhan, D P; Clougherty, P W; Goll, H M; Murray, P A

    1987-07-01

    Our objectives were to investigate the pulmonary vascular effects of exogenously administered bradykinin at normal and reduced levels of cardiac index in intact conscious dogs and to assess the extent to which the pulmonary vascular response to bradykinin is the result of either cyclooxygenase pathway activation or reflex activation of sympathetic beta-adrenergic and -cholinergic receptors. Multipoint pulmonary vascular pressure-cardiac index (P/Q) plots were constructed during normoxia in conscious dogs by step-wise constriction of the thoracic inferior vena cava to reduce Q. In intact dogs, bradykinin (2 micrograms X kg-1 X min-1 iv) caused systemic vasodilation, i.e., systemic arterial pressure was slightly decreased (P less than 0.05), Q was markedly increased (P less than 0.01), and mixed venous PO2 and oxygen saturation (SO2) were increased (P less than 0.01). Bradykinin decreased (P less than 0.01) the pulmonary vascular pressure gradient (pulmonary arterial pressure-pulmonary capillary wedge pressure) over the entire range of Q studied (140-60 ml X min-1 X kg-1) in intact dogs. During cyclooxygenase pathway inhibition with indomethacin, bradykinin again decreased (P less than 0.05) pulmonary arterial pressure-pulmonary capillary wedge pressure at every level of Q, although the magnitude of the vasodilator response was diminished at lower levels of Q (60 ml X min-1 X kg-1). Following combined administration of sympathetic beta-adrenergic and -cholinergic receptor antagonists, bradykinin still decreased (P less than 0.01) pulmonary arterial pressure-pulmonary capillary wedge pressure over the range of Q from 160 to 60 ml X min-1 X kg-1.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:3114215

  1. Modeling climate-wildfire relationships in Southern California

    NASA Astrophysics Data System (ADS)

    Jin, Y.; Randerson, J. T.; Goulden, M.; Faivre, N. R.; Capps, S. B.; Hall, A. D.

    2012-12-01

    Southern California has experienced a series of extraordinarily large and destructive fires over the past decade. Whether fire weather or fuels are the dominant controls for Southern California's fires is still an on-going debate. We here consider the larger picture of wildfire for the entire region and for the past 50 years of fire history. The data used for statistical analysis include monthly precipitation and temperature from PRISM, daily relative humidity and wind speed from a multi-decade reconstruction of climate with MM5 from 1959 to 2007, and California's Fire and Resource Assessment Program (FRAP) historical fire perimeters. 57% of fires occurred in summer (JJA), accounting for 38% of burned area on average. The cumulative precipitation from three previous water years is highly correlated with the number of fires in summer. Relative humidity and temperature, however, explain the most interannual variations in summer burned area. About 49% of burned areas occurred during Santa Ana (SA) events, among which 92% occurred in fall from September to November. Relative humidity during Santa Ana events controls the interannual SA-associated burned areas; number of Santa Ana days and wind speed play additional roles. We built empirical models for both number of fires and burned areas for non-SA and SA fires in summer and fall, respectively. The correlation coefficients between the predicted number of fires and the observations are approximately 0.7. The performance of the statistical model for the burned area is slightly lower. Our results on the contemporary relationships between fire and climate will reduce the uncertainty of predictions of climate change impacts on future fire occurrence and severity.

  2. Structure-activity relationship studies on cholecystokinin: Analogues with partial agonist activity

    SciTech Connect

    Galas, M.C.; Lignon, M.F.; Rodriguez, M.; Mendre, C.; Fulcrand, P.; Laur, J.; Martinez, J. )

    1988-02-01

    In the present study, hepta- and octapeptide analogues of the C-terminal part of cholecystokinin, modified on the C-terminal phenylalanine residue, were synthesized. CCK analogues were prepared in which the peptide bond between aspartic acid and phenylalanine had or had not been modified and were lacking the C-terminal primary amide function. These CCK derivatives were able to cause full stimulation of amylase release from rat pancreatic acini but without a decrease in amylase release at supramaximal concentrations. There was a close relationship between the abilities of these derivatives to stimulate amylase release and their abilities to inhibit binding of {sup 125}I-BH-CCK-9 to CCK receptors on rat and guinea pig pancreatic acini. These CCK analogues were also able to recognize the guinea pig brain CCK receptors, some of them being particularly potent. The findings indicate that the aromatic ring of phenylalanine is important for the binding to brain and pancreatic CCK receptors, whereas the C-terminal primary amide function is not essential for the binding to pancreatic CCK receptors but is crucial for biological activity of rat pancreatic acini.

  3. Obscure phenomena in statistical analysis of quantitative structure-activity relationships. Part 1: Multicollinearity of physicochemical descriptors.

    PubMed

    Mager, P P; Rothe, H

    1990-10-01

    Multicollinearity of physicochemical descriptors leads to serious consequences in quantitative structure-activity relationship (QSAR) analysis, such as incorrect estimators and test statistics of regression coefficients of the ordinary least-squares (OLS) model applied usually to QSARs. Beside the diagnosis of the known simple collinearity, principal component regression analysis (PCRA) also allows the diagnosis of various types of multicollinearity. Only if the absolute values of PCRA estimators are order statistics that decrease monotonically, the effects of multicollinearity can be circumvented. Otherwise, obscure phenomena may be observed, such as good data recognition but low predictive model power of a QSAR model.

  4. Discursive Positionings and Emotions in Modelling Activities

    ERIC Educational Resources Information Center

    Daher, Wajeeh

    2015-01-01

    Mathematical modelling is suggested as an activity through which students engage in meaningful mathematics. In the current research, the modelling activity of a group of four seventh-grade students was analysed using the discursive analysis framework. The research findings show that the positionings and emotions of the group members during their…

  5. A Model for the Supervisor-Doctoral Student Relationship

    ERIC Educational Resources Information Center

    Mainhard, Tim; van der Rijst, Roeland; van Tartwijk, Jan; Wubbels, Theo

    2009-01-01

    The supervisor-doctoral student interpersonal relationship is important for the success of a PhD-project. Therefore, information about doctoral students' perceptions of their relationship with their supervisor can be useful for providing detailed feedback to supervisors aiming at improving the quality of their supervision. This paper describes the…

  6. Hypersensitivity pneumonitis in nonhuman primates: studies on the relationship of immunoregulation and disease activity

    SciTech Connect

    Keller, R.H.; Calvanico, N.J.; Stevens, J.O.

    1982-01-01

    We investigated the relationship of immunoregulation to disease activity in a nonhuman primate model of pigeon breeder's disease. Two Macaca arctoides monkeys developed classical symptoms of hypersensitivity pneumonitis after sensitization and prolonged bronchial challenge, whereas 2 other monkeys remained asymptomatic after in vivo challenge. There were no differences in the percentages of T cells, B cells, monocytes, or FC..gamma..-bearing T cells between symptomatic and asymptomatic animals. Nonetheless, we found a population of concanavalin A-induced, pigeon serum- (PS) induced, and spontaneous T cells that functioned as suppressor cells in autologous in vitro co-cultures in asymptomatic animals that were missing or nonfunctional in symptomatic animals. Monocyte suppressors functioned in both groups. We used low-dose total body irradiation (TBI) to inactivate T suppressor cells. Fifteen radiation units of TBI caused no change in the physical activity, routine chemistries, or blood counts of the 4 animals. After TBI, however, the previously asymptomatic animals developed fever, tachypnea, and signs of pulmonary congestion after in vivo challenge with PS. There was no change in the response to challenge in the symptomatic group. This altered response to in vivo challenge in the previously asymptomatic group persisted for 2 wk after TBI. During this period the difference in in vitro immunoregulatory activity between Con A-induced, PS-induced, and spontaneous T cells in symptomatic and asymptomatic animals disappeared. Monocyte suppressors, however, continued to function in both groups after TBI. these data suggest that the monkey is an appropriate model for studies of human HP and that T cell immunoregulation may be an important element in the pathogenesis and disease activity of HP.

  7. Relationship between ionospheric electric fields and magnetic activity indices

    NASA Astrophysics Data System (ADS)

    Shirapov, D. Sh.

    2012-02-01

    The relations between electric fields in the daytime and nighttime sectors of the polar ionosphere and magnetic activity indices of auroral region (AL) and northern polar cap (PCN) are studied. It is found that the above relations do exist and are described by: a) equations U {pc/(1)} (kV) = 27.62 + 21.43PCN with a correlation coefficient R = 0.87 and U {pc/(1)} (kV) = 4.06 + 49.21PCN - 6.24 PCN2 between the difference in the electric potentials across the polar cap in the daytime sector U {pc/(1)} and PCN and b) regression equation U {pc/(2)} (kV) = 23.33 + 0.08|AL| with R = 0.86 between the difference in the electric potentials across the polar cap in the nighttime sector U {pc/(2)} and |AL|. It is shown that: a) it is possible to use the AL and PCN indices for real-time diagnostics of instantaneous values of the electric fields in the daytime and nighttime sectors of the polar ionosphere in the process of a substorm development; b) at the expansion phase of a substorm, due to calibration of PCN values by the values of the solar wind electric field E sw, the PCN index does not feel the contribution of the western electrojet and, accordingly, the contribution of the nighttime ionospheric electric field U {pc/(2)}, governed by the reconnection in the magnetospheric tail.

  8. Oxazolidinone structure-activity relationships leading to linezolid.

    PubMed

    Barbachyn, Michael R; Ford, Charles W

    2003-05-01

    The development of bacterial resistance to currently available antibacterial agents is a growing global health problem. Of particular concern are infections caused by multidrug-resistant Gram-positive pathogens which are responsible for significant morbidity and mortality in both the hospital and community settings. A number of solutions to the problem of bacterial resistance are possible. The most common approach is to continue modifying existing classes of antibacterial agents to provide new analogues with improved attributes. Other successful strategies are to combine existing antibacterial agents with other drugs as well as the development of improved diagnostic procedures that may lead to rapid identification of the causative pathogen and permit the use of antibacterial agents with a narrow spectrum of activity. Finally, and most importantly, the discovery of novel classes of antibacterial agents employing new mechanisms of action has considerable promise. Such agents would exhibit a lack of cross-resistance with existing antimicrobial drugs. This review describes the work leading to the discovery of linezolid, the first clinically useful oxazolidinone antibacterial agent.

  9. Deterministic Modelling of BAK Activation Kinetics

    NASA Astrophysics Data System (ADS)

    Grills, C.; Chacko, A.; Crawford, N.; Johnston, P. G.; Fennell, D. A.; O'Rourke, S. F. C.

    2009-08-01

    The molecular mechanism underlying mitochondrial BAK activation during apoptosis remains highly controversial. Two seemingly conflicting models have been proposed. In the activation model, BAK requires so-called activating BH3 only proteins (aBH3) to initiate its conformation change. In the other, displacement from inhibitory pro-survival BCL-2 proteins (PBPs) and monomerization of BAK by PBP restricted dissociator BH3-only proteins (dBH3) is sufficient. To better understand the kinetic implications of these models and reconcile these conflicting but highly evidence-based models, we have employed dynamical systems analysis to explore the kinetics underlying BAK activation as a non-linear reaction system. Our findings accommodate both pure agonism and dissociation as mutually exclusive mechanisms capable of initiating BAK activation. In addition we find our work supports a modelling based approach for predicting resistance to therapeutically relevant small molecules BH3 mimetics.

  10. Structure-activity relationships of ketolides vs. macrolides.

    PubMed

    Douthwaite, S

    2001-01-01

    's activity against MLS(B)-resistant respiratory pathogens.

  11. Relationship between Vitamin D Status and Autonomic Nervous System Activity.

    PubMed

    Burt, Morton G; Mangelsdorf, Brenda L; Stranks, Stephen N; Mangoni, Arduino A

    2016-01-01

    Vitamin D deficiency is associated with increased arterial stiffness. However, the mechanisms underlying this association have not been clarified. The aim was to investigate whether changes in autonomic nervous system activity could underlie an association between 25 hydroxy vitamin D and arterial stiffness. A total of 49 subjects (age = 60 ± 8 years, body mass index = 26.7 ± 4.6 kg/m², 25 hydroxy vitamin D = 69 ± 22 nmol/L) underwent measurements of pulse wave velocity (PWV) and augmentation index (AIx), spontaneous baroreflex sensitivity, plasma metanephrines and 25 hydroxy vitamin D. Subjects with 25 hydroxy vitamin D ≤ 50 nmol/L were restudied after 200,000 International Units 25 hydroxy vitamin D. Plasma metanephrine was positively associated with AIx (p = 0.02) independent of age, sex, smoking and cholesterol and negatively associated with 25 hydroxy vitamin D (p = 0.002) independent of age, sex and season. In contrast, there was no association between baroreflex sensitivity and 25 hydroxy vitamin D (p = 0.54). Treatment with vitamin D increased 25 hydroxy vitamin D from 43 ± 5 to 96 ± 24 nmol/L (p < 0.0001) but there was no significant change in plasma metanephrine (115 ± 25 vs. 99 ± 39 pmol/L, p = 0.12). We conclude that as plasma metanephrine was negatively associated with 25 hydroxy vitamin D and positively with AIx, it could mediate an association between these two variables. This hypothesis should be tested in larger interventional studies. PMID:27649235

  12. Relationship between Vitamin D Status and Autonomic Nervous System Activity

    PubMed Central

    Burt, Morton G.; Mangelsdorf, Brenda L.; Stranks, Stephen N.; Mangoni, Arduino A.

    2016-01-01

    Vitamin D deficiency is associated with increased arterial stiffness. However, the mechanisms underlying this association have not been clarified. The aim was to investigate whether changes in autonomic nervous system activity could underlie an association between 25 hydroxy vitamin D and arterial stiffness. A total of 49 subjects (age = 60 ± 8 years, body mass index = 26.7 ± 4.6 kg/m2, 25 hydroxy vitamin D = 69 ± 22 nmol/L) underwent measurements of pulse wave velocity (PWV) and augmentation index (AIx), spontaneous baroreflex sensitivity, plasma metanephrines and 25 hydroxy vitamin D. Subjects with 25 hydroxy vitamin D ≤ 50 nmol/L were restudied after 200,000 International Units 25 hydroxy vitamin D. Plasma metanephrine was positively associated with AIx (p = 0.02) independent of age, sex, smoking and cholesterol and negatively associated with 25 hydroxy vitamin D (p = 0.002) independent of age, sex and season. In contrast, there was no association between baroreflex sensitivity and 25 hydroxy vitamin D (p = 0.54). Treatment with vitamin D increased 25 hydroxy vitamin D from 43 ± 5 to 96 ± 24 nmol/L (p < 0.0001) but there was no significant change in plasma metanephrine (115 ± 25 vs. 99 ± 39 pmol/L, p = 0.12). We conclude that as plasma metanephrine was negatively associated with 25 hydroxy vitamin D and positively with AIx, it could mediate an association between these two variables. This hypothesis should be tested in larger interventional studies. PMID:27649235

  13. Roles and Relationships in Virtual Environments: A Model for Adult Distance Educators Extrapolated from Leadership in Experiences in Virtual Organizations

    ERIC Educational Resources Information Center

    Parchoma, Gale

    2005-01-01

    In this paper, Larkin and Gould's (1999) activity theory methodology for defining work-related roles and Burns' (1963) analysis of organismic organizational form are merged into a model that describes associate and leadership roles and relationships in virtual organizations. The effects of a lack of shared physical space and face-to-face social…

  14. Is the relationship between the built environment and physical activity moderated by perceptions of crime and safety?

    PubMed Central

    2014-01-01

    Background Direct relationships between safety concerns and physical activity have been inconsistently patterned in the literature. To tease out these relationships, crime, pedestrian, and traffic safety were examined as moderators of built environment associations with physical activity. Methods Exploratory analyses used two cross-sectional studies of 2068 adults ages 20–65 and 718 seniors ages 66+ with similar designs and measures. The studies were conducted in the Baltimore, Maryland-Washington, DC and Seattle-King County, Washington regions during 2001–2005 (adults) and 2005–2008 (seniors). Participants were recruited from areas selected to sample high- and low- income and walkability. Independent variables perceived crime, traffic, and pedestrian safety were measured using scales from validated instruments. A GIS-based walkability index was calculated for a street-network buffer around each participant’s home address. Outcomes were total physical activity measured using accelerometers and transportation and leisure walking measured with validated self-reports (IPAQ-long). Mixed effects regression models were conducted separately for each sample. Results Of 36 interactions evaluated across both studies, only 5 were significant (p < .05). Significant interactions did not consistently support a pattern of highest physical activity when safety was rated high and environments were favorable. There was not consistent evidence that safety concerns reduced the beneficial effects of favorable environments on physical activity. Only pedestrian safety showed evidence of a consistent main effect with physical activity outcomes, possibly because pedestrian safety items (e.g., crosswalks, sidewalks) were not as subjective as those on the crime and traffic safety scales. Conclusions Clear relationships between crime, pedestrian, and traffic safety with physical activity levels remain elusive. The development of more precise safety variables and the use of

  15. Capillary pressure – saturation relationships for gas shales measured using a water activity meter

    DOE PAGES

    Donnelly, B.; Perfect, E.; McKay, L. D.; Lemiszki, P. J.; DiStefano, V. H.; Anovitz, L. M.; McFarlane, J.; Hale, R. E.; Cheng, C. -L.

    2016-05-10

    Hydraulic fracturing of gas shale formations involves pumping a large volume of fracking fluid into a hydrocarbon reservoir to fracture the rock and thus increase its permeability. The majority of the fracking fluid introduced is never recovered and the fate of this lost fluid, often called “leak off,” has become the source of much debate. Information on the capillary pressure – saturation relationship for each wetting phase is needed to simulate leak off using numerical reservoir models. The petroleum industry commonly employs air – water capillary pressure – saturation curves to predict these relationships for mixed wet reservoirs. Traditional methodsmore » of measuring this curve are unsuitable for gas shales due to high capillary pressures associated with the small pores present. Still, a possible alternative method is the water activity meter which is used widely in the soil sciences for such measurements. However, its application to lithified material has been limited. Here, this study utilized a water activity meter to measure air – water capillary pressures (ranging from 1.3 to 219.6 MPa) at several water saturation levels in both the wetting and drying directions. Water contents were measured gravimetrically. Seven types of gas producing shale with different porosities (2.5–13.6%) and total organic carbon contents (0.4–13.5%) were investigated. Nonlinear regression was used to fit the resulting capillary pressure – water saturation data pairs for each shale type to the Brooks and Corey equation. Data for six of the seven shale types investigated were successfully fitted (median R2 = 0.93), indicating this may be a viable method for parameterizing capillary pressure – saturation relationships for inclusion in numerical reservoir models. As expected, the different shale types had statistically different Brooks and Corey parameters. However, there were no significant differences between the Brooks and Corey parameters for the wetting and

  16. Quantitative Structure--Activity Relationship (QSAR) for the Oxidation of Trace Organic Contaminants by Sulfate Radical.

    PubMed

    Xiao, Ruiyang; Ye, Tiantian; Wei, Zongsu; Luo, Shuang; Yang, Zhihui; Spinney, Richard

    2015-11-17

    The sulfate radical anion (SO4•–) based oxidation of trace organic contaminants (TrOCs) has recently received great attention due to its high reactivity and low selectivity. In this study, a meta-analysis was conducted to better understand the role of functional groups on the reactivity between SO4•– and TrOCs. The results indicate that compounds in which electron transfer and addition channels dominate tend to exhibit a faster second-order rate constants (kSO4•–) than that of H–atom abstraction, corroborating the SO4•– reactivity and mechanisms observed in the individual studies. Then, a quantitative structure activity relationship (QSAR) model was developed using a sequential approach with constitutional, geometrical, electrostatic, and quantum chemical descriptors. Two descriptors, ELUMO and EHOMO energy gap (ELUMO–EHOMO) and the ratio of oxygen atoms to carbon atoms (#O:C), were found to mechanistically and statistically affect kSO4•– to a great extent with the standardized QSAR model: ln kSO4•– = 26.8–3.97 × #O:C – 0.746 × (ELUMO–EHOMO). In addition, the correlation analysis indicates that there is no dominant reaction channel for SO4•– reactions with various structurally diverse compounds. Our QSAR model provides a robust predictive tool for estimating emerging micropollutants removal using SO4•– during wastewater treatment processes.

  17. The Relationship between Occupational Status and Physical Activity in Korea.

    PubMed

    So, Wi-Young; Yoo, Byoung-Wook; Sung, Dong Jun

    2016-10-01

    This study examined the association between occupational status and physical activity (PA) in Korea. A total of 9,000 Koreans age 10 to 89 years participated in the Korean Survey of Citizens' Sports Participation project in 2012. However, 3,851 participants were excluded from the analysis (housewives, students, and the jobless), providing a sample size of 5,149 participants (3,165 men and 1,984 women) for this study. The association between occupational status and PA was then evaluated using multivariate logistic regression analysis. The odds ratios (ORs; 95% confidence interval [CI]) for reporting at least weekly PA according to job intensity, after adjusting for sex and age, were as follows: moderate-intensity jobs, 1.164 [1.026, 1.320], p = .018; and vigorous-intensity jobs, 1.591 [1.318, 1.921], p < .001, compared with low-intensity jobs as a reference category. For PA intensity in low- and moderate-intensity jobs, after adjusting for sex and age, the ORs (95% CI) were as follows: low-intensity PA, 1.355 [1.033, 1.778], p = .028, moderate PA, 1.227 [1.096, 1.487], p = .002, and vigorous PA, 1.570 [1.213, 2.032], p < .001, compared with sedentary as a reference category. For the intensity of PA among participants with low- or vigorous-intensity jobs, after adjusting for sex and age, the ORs (95% CI) were as follows: low-intensity PA, 1.015 [0.649, 1.586], p = .948, moderate-intensity PA, 1.890 [1.416, 2.522], p < .001, and vigorous-intensity PA, 2.403 [1.395, 4.139], p = .002, compared with sedentary as a reference category. For the intensity of PA between moderate-intensity and vigorous-intensity jobs, after adjusting for sex and age, the ORs (95% CI) were as follows: low-intensity PA, 1.010 [0.759, 1.344], p = .945, moderate-intensity PA, 1.381 [1.136, 1.678], p = .001, and vigorous-intensity PA, 1.595 [1.023, 2.486], p = .039, compared to sedentary as a reference category. The presented findings show a strong association between

  18. Relationship between cefamandole and cefuroxime activity against oxacillin-resistant Staphylococcus epidermidis and oxacillin resistance phenotype.

    PubMed

    Woods, G L; Knapp, C C; Washington, J A

    1987-09-01

    The activity of cefamandole and cefuroxime against oxacillin-resistant staphylococcus epidermidis was studied in vitro to determine whether there was any relationship between oxacillin resistance phenotypes and cephalosporin activity. Oxacillin resistance phenotypes were determined by efficiency-of-plating studies on Mueller-Hinton agar containing oxacillin, with and without NaCl, and incubated at 30 and 35 degrees C. On the basis of MIC and MBC determinations, cefamandole was more active than cefuroxime against oxacillin-resistant S. epidermidis. Although temperature had minimal effect on the activity of either cefamandole or cefuroxime, NaCl significantly decreased the activity of cefuroxime but not of cefamandole. Neither cephalosporin consistently produced greater than or equal to 99.9% bactericidal activity within 24 h in timed killing-curve studies. No consistent relationship was observed between cefamandole or cefuroxime activity and oxacillin resistance phenotype.

  19. Relationship between cefamandole and cefuroxime activity against oxacillin-resistant Staphylococcus epidermidis and oxacillin resistance phenotype.

    PubMed

    Woods, G L; Knapp, C C; Washington, J A

    1987-09-01

    The activity of cefamandole and cefuroxime against oxacillin-resistant staphylococcus epidermidis was studied in vitro to determine whether there was any relationship between oxacillin resistance phenotypes and cephalosporin activity. Oxacillin resistance phenotypes were determined by efficiency-of-plating studies on Mueller-Hinton agar containing oxacillin, with and without NaCl, and incubated at 30 and 35 degrees C. On the basis of MIC and MBC determinations, cefamandole was more active than cefuroxime against oxacillin-resistant S. epidermidis. Although temperature had minimal effect on the activity of either cefamandole or cefuroxime, NaCl significantly decreased the activity of cefuroxime but not of cefamandole. Neither cephalosporin consistently produced greater than or equal to 99.9% bactericidal activity within 24 h in timed killing-curve studies. No consistent relationship was observed between cefamandole or cefuroxime activity and oxacillin resistance phenotype. PMID:3674845

  20. Relationships between fundamental movement skills and objectively measured physical activity in preschool children.

    PubMed

    Cliff, Dylan P; Okely, Anthony D; Smith, Leif M; McKeen, Kim

    2009-11-01

    Gender differences in cross-sectional relationships between fundamental movement skill (FMS) subdomains (locomotor skills, object-control skills) and physical activity were examined in preschool children. Forty-six 3- to 5-year-olds (25 boys) had their FMS video assessed (Test of Gross Motor Development II) and their physical activity objectively monitored (Actigraph 7164 accelerometers). Among boys, object-control skills were associated with physical activity and explained 16.9% (p = .024) and 13.7% (p = .049) of the variance in percent of time in moderate-to-vigorous physical activity (MVPA) and total physical activity, respectively, after controlling for age, SES and z-BMI. Locomotor skills were inversely associated with physical activity among girls, and explained 19.2% (p = .023) of the variance in percent of time in MVPA after controlling for confounders. Gender and FMS subdomain may influence the relationship between FMS and physical activity in preschool children. PMID:20128363

  1. Flavonoids and tyrosine nitration: structure-activity relationship correlation with enthalpy of formation.

    PubMed

    Sadeghipour, Mitra; Terreux, Raphael; Phipps, Jenny

    2005-03-01

    The ability of 11 flavonoids, naturally occurring polyphenols, and their related structure-activity relationships (SAR's) for inhibiting peroxynitrite-induced nitration of tyrosine was investigated. The flavonoids under study could be classified into four groups having very distinct in vitro inhibition effects. We also calculated the heat of formation (DeltaH(f)) of the corresponding flavonoids radicals which supported this finding. The most effective flavonoids included: catechin, taxifolin, luteolin, quercetin, and myricetin which have a common structural feature of ortho-dihydroxyl moiety (3',4'-OH substitution). Naringenin, kaempferol, and morin were 50% less effective inhibitors than the former group of flavonoid while their activities were in the range of trolox (an alpha-tocopherol analogue). The common structural aspect of this group of flavonoids is 4'-OH substitution. Therefore, these two groups of flavonoids may have similar mechanisms for their inhibition activity. No inhibition activity was observed by galangin. Apigenin behaved as a pro-oxidant in our in vitro study. Naringin was as effective as the second group at 4 mM tyrosine concentration while did not illustrate any inhibitory effect at 1 mM concentration of tyrosine. Our study provides further evidence for the importance of the catechol B ring and to a lesser effect the importance of 4'-OH substitution. Moreover, we observed very little or no influence on activity of flavonoids by 3-OH substitution and/or a C2-C3 double bond conjugated with 4-keto group within the subgroup containing the catechol moiety. Theoretical calculation of DeltaDeltaH(f) for tyrosyl radical repair by flavonoids (TyO*+FlOH-->TyOH+FlO*) correlated well with our in vitro results (inhibition% = -10 (DeltaDeltaH(f)), R2=0.906). Furthermore, this correlation was independent of tyrosine concentration. This model can be used to accurately predict the inhibitory effect of flavonoids on nitrotyrosine formation.

  2. Neuroprotective and cognition-enhancing properties of MK-801 flexible analogs. Structure-activity relationships.

    PubMed

    Bachurin, S; Tkachenko, S; Baskin, I; Lermontova, N; Mukhina, T; Petrova, L; Ustinov, A; Proshin, A; Grigoriev, V; Lukoyanov, N; Palyulin, V; Zefirov, N

    2001-06-01

    Neuroprotective and biobehavioral properties of a series of novel open chain MK-801 analogs, as well as their structure-activity relationships have been investigated. Three groups of compounds were synthesized: monobenzylamino, benzhydrylamino, and dibenzylamino (DBA) analogs of MK-801. It was revealed that DBA analogs exhibit pronounced glutamate-induced calcium uptake blocking properties and anti-NMDA activity. The hit compound of DBA series, NT-1505, was investigated for its ability to improve cognition functions in animal model of Alzheimer's disease type dementia, simulated by treating animals with cholinotoxin AF64A. The results from an active avoidance test and a Morris water maze test showed that experimental animals, treated additionally with NT-1505, exhibited much better learning ability and memory than the control group (AF64A treated) and close to that of the vehicle group of animals (treated with physiological solution). Study of NT-1505 influence on locomotor activity revealed that it is characterized by a spectrum of behavioral activity radically different from that of MK-801, and in contrast to the latter one does not produce any psychotomimetic side effects in the therapeutically significant dose interval. The computed docking of MK-801 and its flexible analogs on the NMDA receptor elucidated the crucial role of the hydrogen bond formed between these compounds and the asparagine residue for magnesium binding in the NMDA receptor. It was suggested that strong hydrophobic interaction between MK-801 and the hydrophobic pocket in the NMDA receptor-channel complex determines much higher irreversibility of this adduct compared to the intermediates formed between this site and Mg ions or flexible DBA derivatives, which might explain the absence of PCP-like side effects of the latter compounds.

  3. Relationships between structure and activity of carbon as a multifunctional support for electrocatalysts.

    PubMed

    Stevanović, Sanja I; Panić, Vladimir V; Dekanski, Aleksandar B; Tripković, Amalija V; Jovanović, Vladislava M

    2012-07-14

    We report on new insights into the relationships between structure and activity of glassy carbon (GC), as a model material for electrocatalyst support, during its anodization in acid solution. Our investigation strongly confirms the role of CFGs in promotion of Pt activity by the "spill-over" effect related to CO(ads) for methanol electrooxidation (MEO) on a carbon-supported Pt catalyst. Combined analysis of voltammetric and impedance behaviour as well as changes in GC surface morphology induced by intensification of anodizing conditions reveal an intrinsic influence of the carbon functionalization and the structure of a graphene oxide (GO) layer on the electrical and electrocatalytic properties of activated GC. Although GO continuously grows during anodization, it structurally changes from being a graphite inter-layer within graphite ribbons toward a continuous GO surface layer that deteriorates the native structure of GC. As a consequence of the increased distance between GO-spaced graphite layers, the GC conductivity decreases until the case of profound GO exfoliation under drastic anodizing conditions. This exposes the native, yet abundantly functionalized, GC texture. While GC capacitance continuously increases with intensification of anodizing conditions, the surface nano-roughness and GO resistance reach the highest values at modest anodizing conditions, and then decrease upon drastic anodization due to the onset of GO exfoliation. We found for the first time that the activity of a GC-supported Pt catalyst in MEO, as one of the promising half-reactions in polymer electrolyte fuel cells, strictly follows the changes in GC nano-roughness and GO-induced GC resistance. The highest GC/Pt MEO activity is reached when optimal distance between graphite layers and optimal degree of GC functionalization bring the highest amount of CFGs into intimate contact with the Pt surface. This confirms the promoting role of CFGs in MEO catalysis. PMID:22648036

  4. Relationships between Writing Motivation, Writing Activity, and Writing Performance: Effects of Grade, Sex, and Ability

    ERIC Educational Resources Information Center

    Troia, Gary A.; Harbaugh, Allen G.; Shankland, Rebecca K.; Wolbers, Kimberly A.; Lawrence, Ann M.

    2013-01-01

    A convenience sample of 618 children and adolescents in grades 4 through 10, excluding grade 8, were asked to complete a writing motivation and activity scale and to provide a timed narrative writing sample to permit an examination of the relationships between writing motivation, writing activity, writing performance, and the student…

  5. Relationships between Childhood and Adult Physical Activity Patterns in a Community Sample.

    ERIC Educational Resources Information Center

    Lamarine, Roland J.; Polkinghorne, Ori

    This study examined the relationship between adult physical activity levels and patterns of activity that were established during childhood. A random digit telephone survey was conducted of noninstitutionalized residents in a medium sized California city. Subjects ages 18 and over who volunteered to participate were questioned about their…

  6. Relationship of lactate dehydrogenase activity to body measurements of Angus x Charolais cows and calves

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Objectives were to examine 1) relationships between lactate dehydrogenase (LDH) activity and body measurements of grazing beef cows, and 2) the association between maternal LDH activity in late gestation and subsequent calf birth weight (BRW), hip height (HH) at weaning, and adjusted weaning weight ...

  7. RELATIONSHIPS BETWEEN GIS ENVIRONMENTAL FEATURES AND ADOLESCENT MALE PHYSICAL ACTIVITY: GIS CODING DIFFERENCES

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Background: It is not clear if relationships between GIS obtained environmental features and physical activity differ according to the method used to code GIS data. Methods: Physical activity levels of 210 Boy Scouts were measured by accelerometer. Numbers of parks, trails, gymnasia, bus stops, groc...

  8. Is Father-Child Rough-and-Tumble Play Associated with Attachment or Activation Relationships?

    ERIC Educational Resources Information Center

    Paquette, Daniel; Dumont, Caroline

    2013-01-01

    The activation relationship theory, primarily focused on parental stimulation of risk-taking along with parental control during exploration, predicts that boys will be activated more than girls by their fathers. This theory may explain why fathers engage in rough-and-tumble play (RTP) with children more frequently than mothers, especially with…

  9. The Relationship between Engagement in Cocurricular Activities and Academic Performance: Exploring Gender Differences

    ERIC Educational Resources Information Center

    Zacherman, Avi; Foubert, John

    2014-01-01

    The effects of time spent in cocurricular activities on academic performance was tested. A curvilinear relationship between hours per week spent involved in cocurricular activities and grade point average was discovered such that a low amount of cocurricular involvement was beneficial to grades, while a high amount can potentially hurt academic…

  10. High School Counselors' Perceived Self-Efficacy and Relationships with Actual and Preferred Job Activities

    ERIC Educational Resources Information Center

    Jellison, Vickie Dawn

    2013-01-01

    The purpose of this research was to explore the relationship between School Counselor self-efficacy, role definition and actual and preferred school counseling activities in a sample drawn from a population of school counselors. To measure these variables, the School Counselor Self-Efficacy Scale (SCSE) and the School Counselor Activity Rating…

  11. Relationship between skin temperature and muscle activation during incremental cycle exercise.

    PubMed

    Priego Quesada, Jose I; Carpes, Felipe P; Bini, Rodrigo R; Salvador Palmer, Rosario; Pérez-Soriano, Pedro; Cibrián Ortiz de Anda, Rosa M

    2015-02-01

    While different studies showed that better fitness level adds to the efficiency of the thermoregulatory system, the relationship between muscular effort and skin temperature is still unknown. Therefore, the present study assessed the relationship between neuromuscular activation and skin temperature during cycle exercise. Ten physically active participants performed an incremental workload cycling test to exhaustion while neuromuscular activations were recorded (via surface electromyography - EMG) from rectus femoris, vastus lateralis, biceps femoris and gastrocnemius medialis. Thermographic images were recorded before, immediately after and 10 min after finishing the cycling test, at four body regions of interest corresponding to the muscles where neuromuscular activations were monitored. Frequency band analysis was conducted to assess spectral properties of EMG signals in order to infer on priority in recruitment of motor units. Significant inverse relationship between changes in skin temperature and changes in overall neuromuscular activation for vastus lateralis was observed (r<-0.5 and p<0.04). Significant positive relationship was observed between skin temperature and low frequency components of neuromuscular activation from vastus lateralis (r>0.7 and p<0.01). Participants with larger overall activation and reduced low frequency component for vastus lateralis activation presented a better adaptive response of their thermoregulatory system by showing fewer changes in skin temperature after incremental cycling test.

  12. A Qualitative Investigation of the Relationship between Consumption, Physical Activity, Eating Disorders, and Weight Consciousness

    ERIC Educational Resources Information Center

    Piazza-Gardner, Anna K.; Barry, Adam E.

    2014-01-01

    Background: Previous research has identified a positive relationship between alcohol consumption and disordered eating, alcohol consumption and physical activity, and physical activity and disordered eating. However, there is a paucity of published research examining the interrelatedness of all 3 behaviors together. Purpose: This study examines…

  13. The Relationship Between Passive and Active Vocabularies: Effects of Language Learning Context.

    ERIC Educational Resources Information Center

    Laufer, Batia; Paribakht, T. Sima

    1998-01-01

    Investigated the relationships among three types of vocabulary knowledge (passive, controlled active, and free active) within the same individuals, taking four variables into consideration: passive vocabulary size, language learning context, second (L2) for foreign (FL), length of residence in L2 context, and, among the Canadians, knowledge of…

  14. Structural Relationships between Social Activities and Longitudinal Trajectories of Depression among Older Adults

    ERIC Educational Resources Information Center

    Hong, Song-Iee; Hasche, Leslie; Bowland, Sharon

    2009-01-01

    Purpose: This study examines the structural relationships between social activities and trajectories of late-life depression. Design and Methods: Latent class analysis was used with a nationally representative sample of older adults (N = 5,294) from the Longitudinal Study on Aging II to classify patterns of social activities. A latent growth curve…

  15. The Risky Situation: A Procedure for Assessing the Father-Child Activation Relationship

    ERIC Educational Resources Information Center

    Paquette, Daniel; Bigras, Marc

    2010-01-01

    Initial validation data are presented for the Risky Situation (RS), a 20-minute observational procedure designed to assess the father-child activation relationship with children aged 12-18 months. The coding grid, which is simple and easy to use, allows parent-child dyads to be classified into three categories and provides an activation score. By…

  16. Australian Adolescents' Extracurricular Activity Participation and Positive Development: Is the Relationship Mediated by Peer Attributes?

    ERIC Educational Resources Information Center

    Blomfield, Corey; Barber, Bonnie

    2010-01-01

    Adolescent participation in extracurricular activities is associated with numerous positive outcomes, yet the mechanisms underlying this relationship are largely unknown. This study had two goals: to investigate the association between participation in extracurricular activities and indicators of positive and negative development for Australian…

  17. Fundamental Structure-Activity Relationships of Titanium Dioxide-Based Photocatalysts

    NASA Astrophysics Data System (ADS)

    Roberts, Charles A.

    Heterogeneous photocatalysis has been identified as a means of using renewable solar energy to produce the sustainable, non-carbon fuel H 2 and a variety of useful chemical intermediates. Currently, however, heterogeneous photocatalytic reactions are too inefficient to be industrially relevant and a deeper understanding of the effect of fundamental photocatalytic material properties on photoactivity is needed to further enhance the yields of desired products. In the general field of heterogeneous catalysis, structure-activity relationships aid in the rational design of improved catalysts and this ideology was applied to photocatalytic reactions over TiO2 based photocatalysts and model supported TiO2/SiO2 catalysts in this study. The model supported TiO2/SiO2 catalysts contain well-defined TiOx nanodomain structures that vary in domain size and electronic structure and greatly facilitate the determination of structure-photoactivity relationships. These catalysts were used in reactor studies during photocatalytic water splitting and cyclohexane photo-oxidation, and were monitored for production of H2 and cyclohexanone, respectively. It was found that for both reactions the trend in photoactivity for the TiOx nanodomains proceeded as: pure TiO2 (anatase) (24 nm) > TiO2 (anatase) nanoparticles (4--11 nm) > polymeric surface TiO5 (˜1 nm) > surface isolated TiO4 (˜0.4 nm). Photoluminescence (PL) spectroscopy was employed to yield insight into how exciton generation and recombination are related to TiOx domain size and, thus, to the photoactivity of the examined reactions. Transient PL decay studies determined that the larger bulk structure found in TiO 2 (anatase) nanoparticles (NPs) acts as a reservoir for excitons exhibiting slow recombination kinetics, which have an increased opportunity to participate in photochemistry at the surface active sites. The reactions were also studied using in situ attenuated total reflectance (ATR) Fourier transform infrared

  18. Couple Infertility: From the Perspective of the Close-Relationship Model.

    ERIC Educational Resources Information Center

    Higgins, Barbara S.

    1990-01-01

    Presents Close-Relationship Model as comprehensive framework in which to examine interrelated nature of causes and effects of infertility on marital relationship. Includes these factors: physical and psychological characteristics of both partners; joint, couple characteristics; physical and social environment; and relationship itself. Discusses…

  19. 3D models of slow motions in the Earth's crust and upper mantle in the source zones of seismically active regions and their comparison with highly accurate observational data: I. Main relationships

    NASA Astrophysics Data System (ADS)

    Molodenskii, S. M.; Molodenskii, M. S.; Begitova, T. A.

    2016-09-01

    Constructing detailed models for postseismic and coseismic deformations of the Earth's surface has become particularly important because of the recently established possibility to continuously monitor the tectonic stresses in the source zones based on the data on the time variations in the tidal tilt amplitudes. Below, a new method is suggested for solving the inverse problem about the coseismic and postseismic deformations in the real non-ideally elastic, radially and horizontally heterogeneous, self-gravitating Earth with a hydrostatic distribution of the initial stresses from the satellite data on the ground surface displacements. The solution of this problem is based on decomposing the parameters determining the geometry of the fault surface and the distribution of the dislocation vector on this surface and elastic modules in the source in the orthogonal bases. The suggested approach includes four steps: 1. Calculating (by the perturbation method) the variations in Green's function for the radial and tangential ground surface displacements with small 3D variations in the mechanical parameters and geometry of the source area (i.e., calculating the functional derivatives of the three components of Green's function on the surface from the distributions of the elastic moduli and creep function within the volume of the source area and Burgers' vector on the surface of the dislocations); 2. Successive orthogonalization of the functional derivatives; 3. Passing from the decompositions of the residuals between the observed and modeled surface displacements in the system of nonorthogonalized functional derivatives to their decomposition in the system of orthogonalized derivatives; finding the corrections to the distributions of the sought parameters from the coefficients of their decompositions in the orthogonalized basis; and 4. Analyzing the ambiguity of the inverse problem solution by constructing the orthogonal complement to the obtained basis. The described

  20. Structure-activity relationship (SAR) analysis of a family of steroids acutely controlling steroidogenesis.

    PubMed

    Midzak, Andrew; Rammouz, Georges; Papadopoulos, Vassilios

    2012-11-01

    Steroids metabolically derive from lipid cholesterol, and vertebrate steroids additionally derive from the steroid pregnenolone. Pregnenolone is derived from cholesterol by hydrolytic cleavage of the aliphatic tail by mitochondrial cytochrome P450 enzyme CYP11A1, located in the inner mitochondrial membrane. Delivery of cholesterol to CYP11A1 comprises the principal control step of steroidogenesis, and requires a series of proteins spanning the mitochondrial double membranes. A critical member of this cholesterol translocation machinery is the integral outer mitochondrial membrane translocator protein (18kDa, TSPO), a high-affinity drug- and cholesterol-binding protein. The cholesterol-binding site of TSPO consists of a phylogenetically conserved cholesterol recognition/interaction amino acid consensus (CRAC). Previous studies from our group identified 5-androsten-3β,17,19-triol (19-Atriol) as drug ligand for the TSPO CRAC motif inhibiting cholesterol binding to CRAC domain and steroidogenesis. To further understand 19-Atriol's mechanism of action as well as the molecular recognition by the TSPO CRAC motif, we undertook structure-activity relationship (SAR) analysis of the 19-Atriol molecule with a variety of substituted steroids oxygenated at positions around the steroid backbone. We found that in addition to steroids hydroxylated at carbon C19, hydroxylations at C4, C7, and C11 contributed to inhibition of cAMP-mediated steroidogenesis in a minimal steroidogenic cell model. However, only substituted steroids with C19 hydroxylations exhibited specificity to TSPO, its CRAC motif, and mitochondrial cholesterol transport, as the C4, C7, and C11 hydroxylated steroids inhibited the metabolic transformation of cholesterol by CYP11A1. We thus provide new insights into structure-activity relationships of steroids inhibiting mitochondrial cholesterol transport and steroidogenic cholesterol metabolic enzymes.

  1. Quantitative structure-activity relationships for organophosphates binding to trypsin and chymotrypsin.

    PubMed

    Ruark, Christopher D; Hack, C Eric; Robinson, Peter J; Gearhart, Jeffery M

    2011-01-01

    Organophosphate (OP) nerve agents such as sarin, soman, tabun, and O-ethyl S-[2-(diisopropylamino) ethyl] methylphosphonothioate (VX) do not react solely with acetylcholinesterase (AChE). Evidence suggests that cholinergic-independent pathways over a wide range are also targeted, including serine proteases. These proteases comprise nearly one-third of all known proteases and play major roles in synaptic plasticity, learning, memory, neuroprotection, wound healing, cell signaling, inflammation, blood coagulation, and protein processing. Inhibition of these proteases by OP was found to exert a wide range of noncholinergic effects depending on the type of OP, the dose, and the duration of exposure. Consequently, in order to understand these differences, in silico biologically based dose-response and quantitative structure-activity relationship (QSAR) methodologies need to be integrated. Here, QSAR were used to predict OP bimolecular rate constants for trypsin and α-chymotrypsin. A heuristic regression of over 500 topological/constitutional, geometric, thermodynamic, electrostatic, and quantum mechanical descriptors, using the software Ampac 8.0 and Codessa 2.51 (SemiChem, Inc., Shawnee, KS), was developed to obtain statistically verified equations for the models. General models, using all data subsets, resulted in R(2) values of .94 and .92 and leave-one-out Q(2) values of 0.9 and 0.87 for trypsin and α-chymotrypsin. To validate the general model, training sets were split into independent subsets for test set evaluation. A y-randomization procedure, used to estimate chance correlation, was performed 10,000 times, resulting in mean R(2) values of .24 and .3 for trypsin and α-chymotrypsin. The results show that these models are highly predictive and capable of delineating the complex mechanism of action between OP and serine proteases, and ultimately, by applying this approach to other OP enzyme reactions such as AChE, facilitate the development of biologically based

  2. Quantitative Structure Activity Relationship for Inhibition of Human Organic Cation/Carnitine Transporter (OCTN2)

    PubMed Central

    Diao, Lei; Ekins, Sean; Polli, James E.

    2010-01-01

    Organic cation/carnitine transporter (OCTN2; SLC22A5) is an important transporter for L-carnitine homeostasis, but can be inhibited by drugs, which may cause L-carnitine deficiency and possibly other OCTN2-mediated drug-drug interactions. One objective was to develop a quantitative structure–activity relationship (QSAR) of OCTN2 inhibitors, in order to predict and identify other potential OCTN2 inhibitors and infer potential clinical interactions. A second objective was to assess two high renal clearance drugs that interact with OCTN2 in vitro (cetirizine and cephaloridine) for possible OCTN2-mediated drug-drug interactions. Using previously generated in vitro data of 22 drugs, a 3D quantitative pharmacophore model and a Bayesian machine learning model were developed. The four pharmacophore features include two hydrophobic groups, one hydrogen-bond acceptor, and one positive ionizable center. The Bayesian machine learning model was developed using simple interpretable descriptors and function class fingerprints of maximum diameter 6 (FCFP_6). An external test set of 27 molecules, including 15 newly identified OCTN2 inhibitors, and a literature test set of 22 molecules were used to validate both models. The computational models afforded good capability to identify structurally diverse OCTN2 inhibitors, providing a valuable tool to predict new inhibitors efficiently. Inhibition results confirmed our previously observed association between rhabdomyolysis and Cmax/Ki ratio. The two high renal clearance drugs cetirizine and cephaloridine were found not to be OCTN2 substrates and their diminished elimination by other drugs is concluded not to be mediated by OCTN2. PMID:20831193

  3. Inequity in work and intimate relationships: a Spillover-Crossover model.

    PubMed

    Bakker, Arnold B; Petrou, Paraskevas; Tsaousis, Ioannis

    2012-01-01

    This study among 267 Greek teachers and their partners tested and expanded the recently proposed Spillover-Crossover model (SCM) of well-being. Accordingly, experiences built up at work spill over to the home domain, and then influence the partner. The authors integrated equity theory in the model by formulating hypotheses about exchange in interpersonal relationships. Structural equation modeling analyses supported the spillover hypothesis that teachers who lose their work engagement as a result of an inequitable relationship with their students invest less in the relationship with their partner. In addition, the results supported the crossover hypothesis that teachers' relationship investments, in turn, show a negative relationship with inequity in the intimate relationship as perceived by the partner; and inequity in the intimate relationship contributed to partner depression. The findings are discussed in light of the SCM of well-being. PMID:22059998

  4. Analyzing the Validity of Relationship Banking through Agent-based Modeling

    NASA Astrophysics Data System (ADS)

    Nishikido, Yukihito; Takahashi, Hiroshi

    This article analyzes the validity of relationship banking through agent-based modeling. In the analysis, we especially focus on the relationship between economic conditions and both lenders' and borrowers' behaviors. As a result of intensive experiments, we made the following interesting findings: (1) Relationship banking contributes to reducing bad loan; (2) relationship banking is more effective in enhancing the market growth compared to transaction banking, when borrowers' sales scale is large; (3) keener competition among lenders may bring inefficiency to the market.

  5. USING STRUCTURAL EQUATION MODELING TO INVESTIGATE RELATIONSHIPS AMONG ECOLOGICAL VARIABLES

    EPA Science Inventory

    This paper gives an introductory account of Structural Equation Modeling (SEM) and demonstrates its application using LISREL< with a model utilizing environmental data. Using nine EMAP data variables, we analyzed their correlation matrix with an SEM model. The model characterized...

  6. Developmental relationships as the active ingredient: a unifying working hypothesis of "what works" across intervention settings.

    PubMed

    Li, Junlei; Julian, Megan M

    2012-04-01

    Developmental relationships are characterized by reciprocal human interactions that embody an enduring emotional attachment, progressively more complex patterns of joint activity, and a balance of power that gradually shifts from the developed person in favor of the developing person. The working hypothesis of this article is that developmental relationships constitute the active ingredient of effective interventions serving at-risk children and youth across settings. In the absence of developmental relationships, other intervention elements yield diminished or minimal returns. Scaled-up programs and policies serving children and youth often fall short of their potential impact when their designs or implementation drift toward manipulating other "inactive" ingredients (e.g., incentive, accountability, curricula) instead of directly promoting developmental relationships. Using empirical studies as case examples, this study demonstrates that the presence or absence of developmental relationships distinguishes effective and ineffective interventions for diverse populations across developmental settings. The conclusion is that developmental relationships are the foundational metric with which to judge the quality and forecast the impact of interventions for at-risk children and youth. It is both critical and possible to give foremost considerations to whether program, practice, and policy decisions promote or hinder developmental relationships among those who are served and those who serve.

  7. Derivatives of Ergot-alkaloids: Molecular structure, physical properties, and structure-activity relationships

    NASA Astrophysics Data System (ADS)

    Ivanova, Bojidarka B.; Spiteller, Michael

    2012-09-01

    A comprehensive screening of fifteen functionalized Ergot-alkaloids, containing bulk aliphatic cyclic substituents at D-ring of the ergoline molecular skeleton was performed, studying their structure-active relationships and model interactions with α2A-adreno-, serotonin (5HT2A) and dopamine D3 (D3A) receptors. The accounted high affinity to the receptors binding loops and unusual bonding situations, joined with the molecular flexibility of the substituents and the presence of proton accepting/donating functional groups in the studied alkaloids, may contribute to further understanding the mechanisms of biological activity in vivo and in predicting their therapeutic potential in central nervous system (CNS), including those related the Schizophrenia. Since the presented correlation between the molecular structure and properties, was based on the comprehensively theoretical computational and experimental physical study on the successfully isolated derivatives, through using routine synthetic pathways in a relatively high yields, marked these derivatives as 'treasure' for further experimental and theoretical studied in areas such as: (a) pharmacological and clinical testing; (b) molecular-drugs design of novel psychoactive substances; (c) development of the analytical protocols for determination of Ergot-alkaloids through a functionalization of the ergoline-skeleton, and more.

  8. Structure-antitussive activity relationships of naltrindole derivatives. Identification of novel and potent antitussive agents.

    PubMed

    Sakami, Satoshi; Maeda, Masayuki; Kawai, Koji; Aoki, Takumi; Kawamura, Kuniaki; Fujii, Hideaki; Hasebe, Ko; Nakajima, Mayumi; Endo, Takashi; Ueno, Shinya; Ito, Tsuyoshi; Kamei, Junzo; Nagase, Hiroshi

    2008-08-14

    We have previously reported antitussive effects of naltrindole (NTI), a typical delta opioid receptor antagonist, in a rat model. The ED50 values of NTI by intraperitoneal and peroral injections were 104 microg/kg and 1840 microg/kg, respectively, comparable to those of codeine. Codeine, one of the most reliable centrally acting antitussive drugs, has micro agonist activity and thus the same side effects as morphine, e.g., constipation, dependency, and respiratory depression. Because NTI is a delta opioid antagonist, its derivatives have potential as highly potent antitussives, free from the mu opioid agonist side effects. We attempted to optimize the NTI derivatives to develop novel antitussive agents. On the basis of the studies of structure-antitussive activity relationships of alkyl substituted NTI derivatives, we designed NTI derivatives with extra ring fused structures. As a clinical candidate, we identified a highly potent new compound, (5R,9R,13S,14S)-17-cyclopropylmethyl-6,7-didehydro-4,5-epoxy-5',6'-dihydro-3-methoxy-4'H-pyrrolo[3,2,1-ij]quinolino[2',1':6,7]morphinan-14-ol (5b) methanesulfonate (TRK-850) which was effective even by oral administration (ED50 6.40 microg/kg).

  9. Discursive positionings and emotions in modelling activities

    NASA Astrophysics Data System (ADS)

    Daher, Wajeeh

    2015-11-01

    Mathematical modelling is suggested as an activity through which students engage in meaningful mathematics. In the current research, the modelling activity of a group of four seventh-grade students was analysed using the discursive analysis framework. The research findings show that the positionings and emotions of the group members during their participation in the modelling activity changed as the activity proceeded. Overall, it can be said that three of the four group members acted as insiders, while the fourth acted as an outsider, and only, towards the end of the group's work on the activity, he acted as an insider. Moreover, the research findings point at four factors that affected the group members' positionings and emotions during the modelling activity: the member's characteristics, the member's history of learning experiences, the activity characteristics and the modelling phases. Furthermore, the different positionings of the group members in the different modelling phases were accompanied by different emotions experienced by them, where being an insider and a collaborator resulted in positive emotions, while being an outsider resulted in negative emotions.

  10. The Structure-Activity Relationship of the Antioxidant Peptides from Natural Proteins.

    PubMed

    Zou, Tang-Bin; He, Tai-Ping; Li, Hua-Bin; Tang, Huan-Wen; Xia, En-Qin

    2016-01-12

    Peptides derived from dietary proteins, have been reported to display significant antioxidant activity, which may exert notably beneficial effects in promoting human health and in food processing. Recently, much research has focused on the generation, separation, purification and identification of novel peptides from various protein sources. Some researchers have tried to discover the structural characteristics of antioxidant peptides in order to lessen or avoid the tedious and aimless work involving the ongoing generated peptide preparation schemes. This review aims to summarize the current knowledge on the relationship between the structural features of peptides and their antioxidant activities. The relationship between the structure of the precursor proteins and their abilities to release antioxidant fragments will also be summarized and inferred. The preparation methods and antioxidant capacity evaluation assays of peptides and a prediction scheme of quantitative structure-activity relationship (QSAR) will also be pointed out and discussed.

  11. Quantitative structure-activity relationships and ecological risk assessment: an overview of predictive aquatic toxicology research.

    PubMed

    Bradbury, S P

    1995-09-01

    In the field of aquatic toxicology, quantitative structure-activity relationships (QSARs) have developed as scientifically credible tools for predicting the toxicity of chemicals when little or no empirical data are available. A fundamental understanding of toxicological principles has been considered an important component to the acceptance and application of QSAR approaches as biologically relevant in ecological risk assessments. As a consequence, there has been an evolution of QSAR development and application from that of a chemical-class perspective to one that is more consistent with assumptions regarding modes of toxic action. In this review, techniques to assess modes of toxic action from chemical structure are discussed, with consideration that toxicodynamic knowledge bases must be clearly defined with regard to exposure regimes, biological models/endpoints and compounds that adequately span the diversity of chemicals anticipated for future applications. With such knowledge bases, classification systems, including rule-based expert systems, have been established for use in predictive aquatic toxicology applications. The establishment of QSAR techniques that are based on an understanding of toxic mechanisms is needed to provide a link to physiologically based toxicokinetic and toxicodynamic models, which can provide the means to extrapolate adverse effects across species and exposure regimes. PMID:7570660

  12. Structure-Activity Relationships for Rates of Aromatic Amine Oxidation by Manganese Dioxide.

    PubMed

    Salter-Blanc, Alexandra J; Bylaska, Eric J; Lyon, Molly A; Ness, Stuart C; Tratnyek, Paul G

    2016-05-17

    New energetic compounds are designed to minimize their potential environmental impacts, which includes their transformation and the fate and effects of their transformation products. The nitro groups of energetic compounds are readily reduced to amines, and the resulting aromatic amines are subject to oxidation and coupling reactions. Manganese dioxide (MnO2) is a common environmental oxidant and model system for kinetic studies of aromatic amine oxidation. In this study, a training set of new and previously reported kinetic data for the oxidation of model and energetic-derived aromatic amines was assembled and subjected to correlation analysis against descriptor variables that ranged from general purpose [Hammett σ constants (σ(-)), pKas of the amines, and energies of the highest occupied molecular orbital (EHOMO)] to specific for the likely rate-limiting step [one-electron oxidation potentials (Eox)]. The selection of calculated descriptors (pKa, EHOMO, and Eox) was based on validation with experimental data. All of the correlations gave satisfactory quantitative structure-activity relationships (QSARs), but they improved with the specificity of the descriptor. The scope of correlation analysis was extended beyond MnO2 to include literature data on aromatic amine oxidation by other environmentally relevant oxidants (ozone, chlorine dioxide, and phosphate and carbonate radicals) by correlating relative rate constants (normalized to 4-chloroaniline) to EHOMO (calculated with a modest level of theory). PMID:27074054

  13. Extended Functional Groups (EFG): An Efficient Set for Chemical Characterization and Structure-Activity Relationship Studies of Chemical Compounds.

    PubMed

    Salmina, Elena S; Haider, Norbert; Tetko, Igor V

    2015-01-01

    The article describes a classification system termed "extended functional groups" (EFG), which are an extension of a set previously used by the CheckMol software, that covers in addition heterocyclic compound classes and periodic table groups. The functional groups are defined as SMARTS patterns and are available as part of the ToxAlerts tool (http://ochem.eu/alerts) of the On-line CHEmical database and Modeling (OCHEM) environment platform. The article describes the motivation and the main ideas behind this extension and demonstrates that EFG can be efficiently used to develop and interpret structure-activity relationship models. PMID:26703557

  14. The Relationship Between Parental Physical Activity and Screen Time Behaviors and the Behaviors of their Young Children.

    PubMed

    Carson, Valerie; Stearns, Jodie; Janssen, Ian

    2015-08-01

    The main purpose of this study was to examine the relationships between parental and children's physical activity and screen time behaviors in a large sample of children in the early years. The results are based on 738 children aged 0-5 years and their parents from the Kingston, Canada area. Parents completed a questionnaire from May to September 2011 that assessed sociodemographic characteristics, their physical activity and screen time, and their child's physical activity and screen time. Logistic regression models, adjusted for potential confounders, were conducted. Parents in the lowest quartile of physical activity were 2.77 (95% confidence interval (CI): 1.68-4.57) times more likely to have a child in the lowest quartile of physical activity compared with parents in the highest quartile of physical activity. Relationships were stronger in two parent homes compared with single-parent homes. Parents in the second (odds ratio = 2.27, 95% CI: 1.36-3.78), third (2.30, 1.32-3.99), and fourth (7.47, 4.53-12.33) screen time quartiles were significantly more likely to have a child in the highest quartile of screen time compared with parents in quartile one. To optimize healthy growth and development in the early years, future family-centered interventions targeting both physical activity and screen time appear important.

  15. The Relationship Between Parental Physical Activity and Screen Time Behaviors and the Behaviors of their Young Children.

    PubMed

    Carson, Valerie; Stearns, Jodie; Janssen, Ian

    2015-08-01

    The main purpose of this study was to examine the relationships between parental and children's physical activity and screen time behaviors in a large sample of children in the early years. The results are based on 738 children aged 0-5 years and their parents from the Kingston, Canada area. Parents completed a questionnaire from May to September 2011 that assessed sociodemographic characteristics, their physical activity and screen time, and their child's physical activity and screen time. Logistic regression models, adjusted for potential confounders, were conducted. Parents in the lowest quartile of physical activity were 2.77 (95% confidence interval (CI): 1.68-4.57) times more likely to have a child in the lowest quartile of physical activity compared with parents in the highest quartile of physical activity. Relationships were stronger in two parent homes compared with single-parent homes. Parents in the second (odds ratio = 2.27, 95% CI: 1.36-3.78), third (2.30, 1.32-3.99), and fourth (7.47, 4.53-12.33) screen time quartiles were significantly more likely to have a child in the highest quartile of screen time compared with parents in quartile one. To optimize healthy growth and development in the early years, future family-centered interventions targeting both physical activity and screen time appear important. PMID:25918825

  16. ON THE SCATTER IN THE RADIUS-LUMINOSITY RELATIONSHIP FOR ACTIVE GALACTIC NUCLEI

    SciTech Connect

    Kilerci Eser, E.; Vestergaard, M.; Peterson, B. M.; Denney, K. D.; Bentz, M. C. E-mail: vester@dark-cosmology.dk E-mail: peterson@astronomy.ohio-state.edu

    2015-03-01

    We investigate and quantify the observed scatter in the empirical relationship between the broad line region size R and the luminosity of the active galactic nucleus, in order to better understand its origin. This study is motivated by the indispensable role of this relationship in the mass estimation of cosmologically distant black holes, but may also be relevant to the recently proposed application of this relationship for measuring cosmic distances. We study six nearby reverberation-mapped active galactic nuclei (AGNs) for which simultaneous UV and optical monitoring data exist. We also examine the long-term optical luminosity variations of the Seyfert 1 galaxy NGC 5548 and employ Monte Carlo simulations to study the effects of the intrinsic variability of individual objects on the scatter in the global relationship for a sample of ∼40 AGNs. We find the scatter in this relationship has a correctable dependence on color. For individual AGNs, the size of the Hβ emitting region has a steeper dependence on the nuclear optical luminosity than on the UV luminosity, which can introduce a scatter of ∼0.08 dex into the global relationship, due the nonlinear relationship between the variations in the ionizing continuum and those in the optical continuum. Also, our analysis highlights the importance of understanding and minimizing the scatter in the relationship traced by the intrinsic variability of individual AGNs since it propagates directly into the global relationship. We find that using the UV luminosity as a substitute for the ionizing luminosity can reduce a sizable fraction of the current observed scatter of ∼0.13 dex.

  17. Synthesis and Structure activity relationships of EGCG Analogues, A Recently Identified Hsp90 Inhibitor

    PubMed Central

    Khandelwal, Anuj; Hall, Jessica

    2014-01-01

    Epigallocatechin-3-gallate (EGCG), the principal polyphenol isolated from green tea, was recently shown to inhibit Hsp90, however structure-activity relationships for this natural product have not yet been produced. Herein, we report the synthesis and biological evaluation of EGCG analogues to establish structure-activity relationships between EGCG and Hsp90. All four rings as well as the linker connecting the C- and the D-rings were systematically investigated, which led to the discovery of compounds that inhibit Hs90 and display improvement in efficacy over EGCG. Anti-proliferative activity of all the analogues was determined against MCF-7 and SKBr3 cell lines and Hsp90 inhibitory activity of four most potent analogues was further evaluated by western blot analyses and degradation of Hsp90-dependent client proteins. Prenyl substituted aryl ester of 3,5-dihydroxychroman-3-ol ring system was identified as novel scaffold that exhibit Hsp90 inhibitory activity. PMID:23834230

  18. Synthesis and structure-activity relationships of EGCG analogues, a recently identified Hsp90 inhibitor.

    PubMed

    Khandelwal, Anuj; Hall, Jessica A; Blagg, Brian S J

    2013-08-16

    Epigallocatechin-3-gallate (EGCG), the principal polyphenol isolated from green tea, was recently shown to inhibit Hsp90; however, structure-activity relationships for this natural product have not yet been produced. Herein, we report the synthesis and biological evaluation of EGCG analogues to establish structure-activity relationships between EGCG and Hsp90. All four rings as well as the linker connecting the C- and the D-rings were systematically investigated, which led to the discovery of compounds that inhibit Hs90 and display improvement in efficacy over EGCG. Antiproliferative activity of all the analogues was determined against MCF-7 and SKBr3 cell lines and Hsp90 inhibitory activity of the four most potent analogues was further evaluated by Western blot analyses and degradation of Hsp90-dependent client proteins. The prenyl-substituted aryl ester of 3,5-dihydroxychroman-3-ol ring system was identified as a novel scaffold that exhibits Hsp90 inhibitory activity. PMID:23834230

  19. Toward a Transactional Model of Parent-Adolescent Relationship Quality and Adolescent Psychological Adjustment

    ERIC Educational Resources Information Center

    Fanti, Kostas A.; Henrich, Christopher C.; Brookmeyer, Kathryn A.; Kuperminc, Gabriel P.

    2008-01-01

    The present study includes externalizing problems, internalizing problems, mother-adolescent relationship quality, and father-adolescent relationship quality in the same structural equation model and tests the longitudinal reciprocal association among all four variables over a 1-year period. A transactional model in which adolescents'…

  20. Macrolide-Based Microtubule-Stabilizing Agents - Chemistry and Structure-Activity Relationships

    NASA Astrophysics Data System (ADS)

    Pfeiffer, B.; Kuzniewski, C. N.; Wullschleger, C.; Altmann, K.-H.

    This article provides an overview on the chemistry and structure-activity relationships of macrolide-based microtubule-stabilizing agents. The primary focus will be on the total synthesis or examples thereof, but a brief summary of the current state of knowledge on the structure-activity relationships of epothilones, laulimalide, dictyostatin, and peloruside A will also be given. This macrolide class of compounds, over the last decade, has become the subject of growing interest due to their ability to inhibit human cancer cell proliferation through a taxol-like mechanism of action.

  1. Relationship between High-Performance Liquid Chromatography Fingerprints and Uric Acid-Lowering Activities of Cichorium intybus L.

    PubMed

    Zhu, Chun-Sheng; Zhang, Bing; Lin, Zhi-Jian; Wang, Xue-Jie; Zhou, Yue; Sun, Xiao-Xia; Xiao, Ming-Liang

    2015-01-01

    This study aimed to explore the spectrum-effect relationships between high-performance liquid chromatography fingerprints and the uric acid-lowering activities of chicory. Chemical fingerprints of chicory samples from ten different sources were determined by high-performance liquid chromatography, and then investigated by similarity analysis and hierarchical clustering analysis. Pharmacodynamics experiments were conducted in animals to obtain the uric acid-lowering activity information of each chicory sample. The spectrum-effect relationships between chemical fingerprints and the uric acid-lowering activities of chicory were established by canonical correlation analysis. The structures of potential effective peaks were identified by liquid chromatography with tandem mass spectrometry. The results showed that a close correlation existed between the spectrum and effect of chicory. Aesculin, chlorogenic acid, chicoric acid, isochlorogenic acid A/B/C and 13,14-seco-stigma5(6),14(15)-diene-3α-ol might be the main effective constituents. This work provides a general model of the combination of high-performance liquid chromatography and uric acid-lowering activities to study the spectrum-effect relationships of chicory, which can be used to discover the principle components responsible for the bioactivity. PMID:26007193

  2. Relationship between High-Performance Liquid Chromatography Fingerprints and Uric Acid-Lowering Activities of Cichorium intybus L.

    PubMed

    Zhu, Chun-Sheng; Zhang, Bing; Lin, Zhi-Jian; Wang, Xue-Jie; Zhou, Yue; Sun, Xiao-Xia; Xiao, Ming-Liang

    2015-05-22

    This study aimed to explore the spectrum-effect relationships between high-performance liquid chromatography fingerprints and the uric acid-lowering activities of chicory. Chemical fingerprints of chicory samples from ten different sources were determined by high-performance liquid chromatography, and then investigated by similarity analysis and hierarchical clustering analysis. Pharmacodynamics experiments were conducted in animals to obtain the uric acid-lowering activity information of each chicory sample. The spectrum-effect relationships between chemical fingerprints and the uric acid-lowering activities of chicory were established by canonical correlation analysis. The structures of potential effective peaks were identified by liquid chromatography with tandem mass spectrometry. The results showed that a close correlation existed between the spectrum and effect of chicory. Aesculin, chlorogenic acid, chicoric acid, isochlorogenic acid A/B/C and 13,14-seco-stigma5(6),14(15)-diene-3α-ol might be the main effective constituents. This work provides a general model of the combination of high-performance liquid chromatography and uric acid-lowering activities to study the spectrum-effect relationships of chicory, which can be used to discover the principle components responsible for the bioactivity.

  3. The Soul Mates Model: A Seven-Stage Model for Couple's Long-Term Relationship Development and Flourishing

    ERIC Educational Resources Information Center

    De La Lama, Luisa Batthyany; De La Lama, Luis; Wittgenstein, Ariana

    2012-01-01

    This article presents the integrative soul mates relationship development model, which provides the helping professionals with a conceptual map for couples' relationship development from dating, to intimacy, to soul mating, and long-term flourishing. This model is informed by a holistic, a developmental, and a positive psychology conceptualization…

  4. Interpersonal distance modeling during fighting activities.

    PubMed

    Dietrich, Gilles; Bredin, Jonathan; Kerlirzin, Yves

    2010-10-01

    The aim of this article is to elaborate a general framework for modeling dual opposition activities, or more generally, dual interaction. The main hypothesis is that opposition behavior can be measured directly from a global variable and that the relative distance between the two subjects can be this parameter. Moreover, this parameter should be considered as multidimensional parameter depending not only on the dynamics of the subjects but also on the "internal" parameters of the subjects, such as sociological and/or emotional states. Standard and simple mechanical formalization will be used to model this multifactorial distance. To illustrate such a general modeling methodology, this model was compared with actual data from an opposition activity like Japanese fencing (kendo). This model captures not only coupled coordination, but more generally interaction in two-subject activities. PMID:21051791

  5. Modelling Inter-relationships among water, governance, human development variables in developing countries with Bayesian networks.

    NASA Astrophysics Data System (ADS)

    Dondeynaz, C.; Lopez-Puga, J.; Carmona-Moreno, C.

    2012-04-01

    Improving Water and Sanitation Services (WSS), being a complex and interdisciplinary issue, passes through collaboration and coordination of different sectors (environment, health, economic activities, governance, and international cooperation). This inter-dependency has been recognised with the adoption of the "Integrated Water Resources Management" principles that push for the integration of these various dimensions involved in WSS delivery to ensure an efficient and sustainable management. The understanding of these interrelations appears as crucial for decision makers in the water sector in particular in developing countries where WSS still represent an important leverage for livelihood improvement. In this framework, the Joint Research Centre of the European Commission has developed a coherent database (WatSan4Dev database) containing 29 indicators from environmental, socio-economic, governance and financial aid flows data focusing on developing countries (Celine et al, 2011 under publication). The aim of this work is to model the WatSan4Dev dataset using probabilistic models to identify the key variables influencing or being influenced by the water supply and sanitation access levels. Bayesian Network Models are suitable to map the conditional dependencies between variables and also allows ordering variables by level of influence on the dependent variable. Separated models have been built for water supply and for sanitation because of different behaviour. The models are validated if complying with statistical criteria but either with scientific knowledge and literature. A two steps approach has been adopted to build the structure of the model; Bayesian network is first built for each thematic cluster of variables (e.g governance, agricultural pressure, or human development) keeping a detailed level for interpretation later one. A global model is then built based on significant indicators of each cluster being previously modelled. The structure of the

  6. Investigating Nitrogen Pollution: Activities and Models.

    ERIC Educational Resources Information Center

    Green Teacher, 2000

    2000-01-01

    Introduces activities on nitrogen, nitrogen pollution from school commuters, nitrogen response in native and introduced species, and nutrient loading models. These activities help students determine the nitrogen contribution from their parents' cars, test native plant responses to nitrogen, and experiment with the results of removing water from…

  7. Non-linear quantitative structure-activity relationship for adenine derivatives as competitive inhibitors of adenosine deaminase

    SciTech Connect

    Sadat Hayatshahi, Sayyed Hamed; Khajeh, Khosro

    2005-12-16

    Logistic regression and artificial neural networks have been developed as two non-linear models to establish quantitative structure-activity relationships between structural descriptors and biochemical activity of adenosine based competitive inhibitors, toward adenosine deaminase. The training set included 24 compounds with known k {sub i} values. The models were trained to solve two-class problems. Unlike the previous work in which multiple linear regression was used, the highest of positive charge on the molecules was recognized to be in close relation with their inhibition activity, while the electric charge on atom N1 of adenosine was found to be a poor descriptor. Consequently, the previously developed equation was improved and the newly formed one could predict the class of 91.66% of compounds correctly. Also optimized 2-3-1 and 3-4-1 neural networks could increase this rate to 95.83%.

  8. Relationship between Resilience, Psychological Distress and Physical Activity in Cancer Patients: A Cross-Sectional Observation Study

    PubMed Central

    Matzka, Martin; Mayer, Hanna; Köck-Hódi, Sabine; Moses-Passini, Christina; Dubey, Catherine; Jahn, Patrick; Schneeweiss, Sonja; Eicher, Manuela

    2016-01-01

    Objective Psychological distress remains a major challenge in cancer care. The complexity of psychological symptoms in cancer patients requires multifaceted symptom management tailored to individual patient characteristics and active patient involvement. We assessed the relationship between resilience, psychological distress and physical activity in cancer patients to elucidate potential moderators of the identified relationships. Method A cross-sectional observational study to assess the prevalence of symptoms and supportive care needs of oncology patients undergoing chemotherapy, radiotherapy or chemo-radiation therapy in a tertiary oncology service. Resilience was assessed using the 10-item Connor-Davidson Resilience Scale (CD-RISC 10), social support was evaluated using the 12-item Multidimensional Scale of Perceived Social Support (MSPSS) and both psychological distress and activity level were measured using corresponding subscales of the Rotterdam Symptom Checklist (RSCL). Socio-demographic and medical data were extracted from patient medical records. Correlation analyses were performed and structural equation modeling was employed to assess the associations between resilience, psychological distress and activity level as well as selected socio-demographic variables. Results Data from 343 patients were included in the analysis. Our revised model demonstrated an acceptable fit to the data (χ2(163) = 313.76, p = .000, comparative fit index (CFI) = .942, Tucker-Lewis index (TLI) = .923, root mean square error of approximation (RMSEA) = .053, 90% CI [.044.062]). Resilience was negatively associated with psychological distress (β = -.59), and positively associated with activity level (β = .20). The relationship between resilience and psychological distress was moderated by age (β = -0.33) but not social support (β = .10, p = .12). Conclusion Cancer patients with higher resilience, particularly older patients, experience lower psychological distress. Patients

  9. Working Models about Mother-Child Relationships in Abandoned Children.

    ERIC Educational Resources Information Center

    Garcia-Torres, Belen; Guerrero, Pilar Garcia-Calvo

    2000-01-01

    Sixty abandoned and 36 non-abandoned school-aged children were told six short stories about mother-child relationships. Abandoned children showed less positive affect attribution to the mother, more compliant behavior in the child, and more justification of the mother when her behaviors were unfair. (Contains references.) (Author/CR)

  10. Modeling Best Practice through Online Learning: Building Relationships

    ERIC Educational Resources Information Center

    Cerniglia, Ellen G.

    2011-01-01

    Students may fear that they will feel unsupported and isolated when engaged in online learning. They don't know how they will be able to build relationships with their teacher and classmates solely based on written words, without facial expressions, tone of voice, and other nonverbal communication cues. Traditionally, online learning required…

  11. The Force-Frequency Relationship: Insights from Mathematical Modeling

    ERIC Educational Resources Information Center

    Puglisi, Jose L.; Negroni, Jorge A.; Chen-Izu, Ye; Bers, Donald M.

    2013-01-01

    The force-frequency relationship has intrigued researchers since its discovery by Bowditch in 1871. Many attempts have been made to construct mathematical descriptions of this phenomenon, beginning with the simple formulation of Koch-Wesser and Blinks in 1963 to the most sophisticated ones of today. This property of cardiac muscle is amplified by…

  12. Adolescents' working models and styles for relationships with parents, friends, and romantic partners.

    PubMed

    Furman, Wyndol; Simon, Valerie A; Shaffer, Laura; Bouchey, Heather A

    2002-01-01

    This study examined the links among adolescents' representations of their relationships with parents, friends, and romantic partners. Sixty-eight adolescents were interviewed three times to assess their working models for each of these types of relationships. Working models of friendships were related to working models of relationships with parents and romantic partners. Working models of relationships with parents and romantic partners were inconsistently related. A similar pattern of results was obtained for self-report measures of relational styles for the three types of relationships. Perceived experiences were also related. Specifically, support in relationships with parents tended to be related to support in romantic relationships and friendships, but the latter two were unrelated. On the other hand, self and other controlling behaviors in friendships were related to corresponding behaviors in romantic relationships. Negative interactions in the three types of relationships also tended to be related. Taken together, the findings indicate that the representations of the three types of relationships are distinct, yet related. Discussion focuses on the nature of the links among the three.

  13. A relational learning approach to Structure-Activity Relationships in drug design toxicity studies.

    PubMed

    Camacho, Rui; Pereira, Max; Costa, Vítor Santos; Fonseca, Nuno A; Adriano, Carlos; Simões, Carlos J V; Brito, Rui M M

    2011-09-16

    It has been recognized that the development of new therapeutic drugs is a complex and expensive process. A large number of factors affect the activity in vivo of putative candidate molecules and the propensity for causing adverse and toxic effects is recognized as one of the major hurdles behind the current "target-rich, lead-poor" scenario. Structure-Activity Relationship (SAR) studies, using relational Machine Learning (ML) algorithms, have already been shown to be very useful in the complex process of rational drug design. Despite the ML successes, human expertise is still of the utmost importance in the drug development process. An iterative process and tight integration between the models developed by ML algorithms and the know-how of medicinal chemistry experts would be a very useful symbiotic approach. In this paper we describe a software tool that achieves that goal--iLogCHEM. The tool allows the use of Relational Learners in the task of identifying molecules or molecular fragments with potential to produce toxic effects, and thus help in stream-lining drug design in silico. It also allows the expert to guide the search for useful molecules without the need to know the details of the algorithms used. The models produced by the algorithms may be visualized using a graphical interface, that is of common use amongst researchers in structural biology and medicinal chemistry. The graphical interface enables the expert to provide feedback to the learning system. The developed tool has also facilities to handle the similarity bias typical of large chemical databases. For that purpose the user can filter out similar compounds when assembling a data set. Additionally, we propose ways of providing background knowledge for Relational Learners using the results of Graph Mining algorithms.

  14. A geographic sampling strategy for studying relationships between human activity and malaria vectors in urban Africa.

    PubMed

    Keating, Joseph; MacIntyre, Kate; Mbogo, Charles; Githeko, Andrew; Regens, James L; Swalm, Chris; Ndenga, Bryson; Steinberg, Laura J; Kibe, Lydiah; Githure, John I; Beier, John C

    2003-03-01

    This paper describes a geographic sampling strategy for ecologic studies and describes the relationship between human activities and anopheline larval ecology in urban areas. Kisumu and Malindi, Kenya were mapped using global positioning systems, and a geographic information system was used to overlay a measured grid, which served as a sampling frame. Grid cells were stratified and randomly selected according to levels of planning and drainage. A cross-sectional survey was conducted in April and May 2001 to collect entomologic and human ecologic data. Multivariate regression analysis was used to test the relationship between the abundance of potential larval habitats, and house density, socioeconomic status, and planning and drainage. In Kisumu, 98 aquatic habitats were identified, 65% of which were human made and 39% were positive for anopheline larvae. In Malindi, 91 aquatic habitats were identified, of which, 93% were human made and 65% were harboring anopheline larvae. The regression model explains 82% of the variance associated with the abundance of potential larval habitats in Kisumu. In Malindi, 59% of the variance was explained. As the number of households increased, the number of larval habitats increased correspondingly to a point. Beyond a critical threshold, the density of households appeared to suppress the development of aquatic habitats. The proportion of high-income households and the planning and drainage variables tested insignificant in both locations. The integration of social and biologic sciences will allow local mosquito and malaria control groups an opportunity to assess the risk of encountering potentially infectious mosquitoes in a given area, and concentrate resources accordingly.

  15. Chemical graphs, molecular matrices and topological indices in chemoinformatics and quantitative structure-activity relationships.

    PubMed

    Ivanciuc, Ovidiu

    2013-06-01

    Chemical and molecular graphs have fundamental applications in chemoinformatics, quantitative structureproperty relationships (QSPR), quantitative structure-activity relationships (QSAR), virtual screening of chemical libraries, and computational drug design. Chemoinformatics applications of graphs include chemical structure representation and coding, database search and retrieval, and physicochemical property prediction. QSPR, QSAR and virtual screening are based on the structure-property principle, which states that the physicochemical and biological properties of chemical compounds can be predicted from their chemical structure. Such structure-property correlations are usually developed from topological indices and fingerprints computed from the molecular graph and from molecular descriptors computed from the three-dimensional chemical structure. We present here a selection of the most important graph descriptors and topological indices, including molecular matrices, graph spectra, spectral moments, graph polynomials, and vertex topological indices. These graph descriptors are used to define several topological indices based on molecular connectivity, graph distance, reciprocal distance, distance-degree, distance-valency, spectra, polynomials, and information theory concepts. The molecular descriptors and topological indices can be developed with a more general approach, based on molecular graph operators, which define a family of graph indices related by a common formula. Graph descriptors and topological indices for molecules containing heteroatoms and multiple bonds are computed with weighting schemes based on atomic properties, such as the atomic number, covalent radius, or electronegativity. The correlation in QSPR and QSAR models can be improved by optimizing some parameters in the formula of topological indices, as demonstrated for structural descriptors based on atomic connectivity and graph distance. PMID:23701000

  16. Modelling the Active Hearing Process in Mosquitoes

    NASA Astrophysics Data System (ADS)

    Avitabile, Daniele; Homer, Martin; Jackson, Joe; Robert, Daniel; Champneys, Alan

    2011-11-01

    A simple microscopic mechanistic model is described of the active amplification within the Johnston's organ of the mosquito species Toxorhynchites brevipalpis. The model is based on the description of the antenna as a forced-damped oscillator coupled to a set of active threads (ensembles of scolopidia) that provide an impulsive force when they twitch. This twitching is in turn controlled by channels that are opened and closed if the antennal oscillation reaches a critical amplitude. The model matches both qualitatively and quantitatively with recent experiments. New results are presented using mathematical homogenization techniques to derive a mesoscopic model as a simple oscillator with nonlinear force and damping characteristics. It is shown how the results from this new model closely resemble those from the microscopic model as the number of threads approach physiologically correct values.

  17. Electromagnetic modeling of active silicon nanocrystal waveguides.

    PubMed

    Redding, Brandon; Shi, Shouyuan; Creazzo, Tim; Prather, Dennis W

    2008-06-01

    In this paper we propose an electromagnetic analysis of active silicon nano-crystal (Si-nc) waveguide devices. To account for the nonlinearity in the active medium we introduce a four level rate equation model whose parameters are based on experimentally reported material properties. The electromagnetic polarization serves to couple the quantum mechanical and electromagnetic behavior within the ADE-FDTD scheme. The developed modeling tool is used to simulate waveguide amplifiers, enhanced spontaneous emission microcavities, and the temporal lasing dynamics of active Si-nc based devices.

  18. THE USE OF STRUCTURE-ACTIVITY RELATIONSHIPS IN INTEGRATING THE CHEMISTRY AND TOXICOLOGY OF ENDOCRINE DISRUPTING CHEMICALS

    EPA Science Inventory

    Structure activity relationships (SARs) are based on the principle that structurally similar chemicals should have similar biological activity. SARs relate specifically-defined toxicological activity of chemicals to their molecular structure and physico-chemical properties. To de...

  19. Oxidative Dehydrogenation on Nanocarbon: Intrinsic Catalytic Activity and Structure-Function Relationships.

    PubMed

    Qi, Wei; Liu, Wei; Guo, Xiaoling; Schlögl, Robert; Su, Dangsheng

    2015-11-01

    Physical and chemical insights into the nature and quantity of the active sites and the intrinsic catalytic activity of nanocarbon materials in alkane oxidative dehydrogenation (ODH) reactions are reported using a novel in situ chemical titration process. A study on the structure-function relationship reveals that the active sites are identical both in nature and function on various nanocarbon catalysts. Additionally, the quantity of the active sites could be used as a metric to normalize the reaction rates, and thus to evaluate the intrinsic activity of nanocarbon catalysts. The morphology of the nanocarbon catalysts at the microscopic scale exhibits a minor influence on their intrinsic ODH catalytic activity. The number of active sites calculated from the titration process indicates the number of catalytic centers that are active (that is, working) under the reaction conditions. PMID:26388451

  20. QSAR models for anti-malarial activity of 4-aminoquinolines.

    PubMed

    Masand, Vijay H; Toropov, Andrey A; Toropova, Alla P; Mahajan, Devidas T

    2014-03-01

    In the present study, predictive quantitative structure - activity relationship (QSAR) models for anti-malarial activity of 4-aminoquinolines have been developed. CORAL, which is freely available on internet (http://www.insilico.eu/coral), has been used as a tool of QSAR analysis to establish statistically robust QSAR model of anti-malarial activity of 4-aminoquinolines. Six random splits into the visible sub-system of the training and invisible subsystem of validation were examined. Statistical qualities for these splits vary, but in all these cases, statistical quality of prediction for anti-malarial activity was quite good. The optimal SMILES-based descriptor was used to derive the single descriptor based QSAR model for a data set of 112 aminoquinolones. All the splits had r(2)> 0.85 and r(2)> 0.78 for subtraining and validation sets, respectively. The three parametric multilinear regression (MLR) QSAR model has Q(2) = 0.83, R(2) = 0.84 and F = 190.39. The anti-malarial activity has strong correlation with presence/absence of nitrogen and oxygen at a topological distance of six. PMID:24801104

  1. A Kinetic Model of Active Extensile Bundles

    NASA Astrophysics Data System (ADS)

    Goldstein, Daniel; Chakraborty, Bulbul; Baskaran, Aparna

    Recent experiments in active filament networks reveal interesting rheological properties (Dan Chen: APS March Meeting 2015 D49.00001). This system consumes ATP to produce an extensile motion in bundles of microtubules. This extension then leads to self generated stresses and spontaneous flows. We propose a minimal model where the activity is modeled by self-extending bundles that are part of a cross linked network. This network can reorganize itself through buckling of extending filaments and merging events that alter the topology of the network. We numerically simulate this minimal kinetic model and examine the emergent rheological properties and determine how stresses are generated by the extensile activity. We will present results that focus on the effects of confinement and network connectivity of the bundles on stress fluctuations and response of an active gel.

  2. Semisynthesis and quantitative structure-activity relationship (QSAR) study of some cholesterol-based hydrazone derivatives as insecticidal agents.

    PubMed

    Yang, Chun; Shao, Yonghua; Zhi, Xiaoyan; Huan, Qu; Yu, Xiang; Yao, Xiaojun; Xu, Hui

    2013-09-01

    In continuation of our program aimed at the discovery and development of natural-product-based insecticidal agents, four series of novel cholesterol-based hydrazone derivatives were synthesized, and their insecticidal activity was tested against the pre-third-instar larvae of oriental armyworm, Mythimna separata (Walker) in vivo at 1mg/mL. All the derivatives showed the better insecticidal activity than their precursor cholesterol. Quantitative structure-activity relationship (QSAR) model demonstrated that six descriptors such as RDF085v, Mor06u, Mor11u, Dv, HATS0v and H-046, are likely to influence the insecticidal activity of these compounds. Among them, two important ones are the Mor06u and RDF085v.

  3. Flavonoids promoting HaCaT migration: I. Hologram quantitative structure-activity relationships.

    PubMed

    Cho, Moonjae; Yoon, Hyuk; Park, Mijoo; Kim, Young Hwa; Lim, Yoongho

    2014-03-15

    Cell migration plays an important role in multicellular development and preservation. Because wound healing requires cell migration, compounds promoting cell migration can be used for wound repair therapy. Several plant-derived polyphenols are known to promote cell migration, which improves wound healing. Previous studies of flavonoids on cell lines have focused on their inhibitory effects and not on wound healing. In addition, studies of flavonoids on wound healing have been performed using mixtures. In this study, individual flavonoids were used for cellular migration measurements. Relationships between the cell migration effects of flavonoids and their structural properties have never been reported. Here, we investigated the migration of keratinocytes caused by 100 flavonoids and examined their relationships using hologram quantitative structure-activity relationships. The structural conditions responsible for efficient cell migration on keratinocyte cell lines determined from the current study will facilitate the design of flavonoids with improved activity.

  4. The Relationship between Physical Activity and Bone during Adolescence Differs according to Sex and Biological Maturity.

    PubMed

    Weeks, Benjamin K; Beck, Belinda R

    2010-01-01

    This study examines the relationships between bone mass, physical activity, and maturational status in healthy adolescent boys and girls. Methods. Ninety-nine early high-school (Year 9) students were recruited. Physical activity and other lifestyle habits were recorded via questionnaire. Anthropometrics, muscle power, calcaneal broadband ultrasound attenuation (BUA), bone mineral content (BMC), and lean tissue mass were measured. Maturity was determined by Tanner stage and estimated age of peak height velocity (APHV). Results. Boys had greater APHV, weight, height, muscle power, and dietary calcium than girls (P < .05). Boys exhibited greater femoral neck BMC and trochanteric BMC while girls had higher BUA and spine BMAD (P < .05). Physical activity and vertical jump predicted BMAD and BUA most strongly for boys whereas years from APHV were the strongest predictor for girls. Conclusion. Sex-specific relationships exist between physical activity, maturity and bone mass during adolescence.

  5. Quantitative Structure--Activity Relationship (QSAR) for the Oxidation of Trace Organic Contaminants by Sulfate Radical.

    PubMed

    Xiao, Ruiyang; Ye, Tiantian; Wei, Zongsu; Luo, Shuang; Yang, Zhihui; Spinney, Richard

    2015-11-17

    The sulfate radical anion (SO4•–) based oxidation of trace organic contaminants (TrOCs) has recently received great attention due to its high reactivity and low selectivity. In this study, a meta-analysis was conducted to better understand the role of functional groups on the reactivity between SO4•– and TrOCs. The results indicate that compounds in which electron transfer and addition channels dominate tend to exhibit a faster second-order rate constants (kSO4•–) than that of H–atom abstraction, corroborating the SO4•– reactivity and mechanisms observed in the individual studies. Then, a quantitative structure activity relationship (QSAR) model was developed using a sequential approach with constitutional, geometrical, electrostatic, and quantum chemical descriptors. Two descriptors, ELUMO and EHOMO energy gap (ELUMO–EHOMO) and the ratio of oxygen atoms to carbon atoms (#O:C), were found to mechanistically and statistically affect kSO4•– to a great extent with the standardized QSAR model: ln kSO4•– = 26.8–3.97 × #O:C – 0.746 × (ELUMO–EHOMO). In addition, the correlation analysis indicates that there is no dominant reaction channel for SO4•– reactions with various structurally diverse compounds. Our QSAR model provides a robust predictive tool for estimating emerging micropollutants removal using SO4•– during wastewater treatment processes. PMID:26451961

  6. Discovery of novel glitazones incorporated with phenylalanine and tyrosine: synthesis, antidiabetic activity and structure-activity relationships.

    PubMed

    Prashantha Kumar, B R; Baig, Nasir R; Sudhir, Sai; Kar, Koyal; Kiranmai, M; Pankaj, M; Joghee, Nanjan M

    2012-12-01

    We report a series of new glitazones incorporated with phenylalanine and tyrosine. All the compounds were tested for their in vitro glucose uptake activity using rat-hemidiaphragm, both in presence and absence of insulin. Six of the most active compounds from the in vitro screening were taken forward for their in vivo triglyceride and glucose lowering activity against dexamethazone induced hyperlipidemia and insulin resistance in Wistar rats. The liver samples of rats that received the most active compounds, 23 and 24, in the in vivo studies, were subjected to histopathological examination to assess their short term hepatotoxicity. The investigations on the in vitro glucose uptake, in vivo triglyceride and glucose lowering activity are described here along with the quantitative structure-activity relationships.

  7. Structure-activity relationship study of dibenzocyclooctadiene lignans isolated from Schisandra chinensis on lipopolysaccharide-induced microglia activation.

    PubMed

    Hu, Di; Han, Na; Yao, Xuechun; Liu, Zhihui; Wang, Yu; Yang, Jingyu; Yin, Jun

    2014-06-01

    To explore the relationship of the dibenzocyclooctadiene lignans from Schisandra chinensis to their anti-inflammatory activities, series of dibenzocyclooctadiene lignans were isolated and assessed by testing their inhibitory effects on nitric oxide production in lipopolysaccharide-induced BV2 mouse microglia. It was found, for the first time, that dibenzocyclooctadiene lignans which have S-biphenyl and methylenedioxy groups strongly inhibited LPS-induced microglia activation. The methoxy group on the cyclooctadiene introduced more effectiveness, but the presence of an acetyl group on the cyclooctadiene or hydroxyl group on C-7 decreased the inhibitory activity.

  8. Identifying and Evaluating the Relationships that Control a Land Surface Model's Hydrological Behavior

    NASA Technical Reports Server (NTRS)

    Koster, Randal D.; Mahanama, Sarith P.

    2012-01-01

    The inherent soil moisture-evaporation relationships used in today 's land surface models (LSMs) arguably reflect a lot of guesswork given the lack of contemporaneous evaporation and soil moisture observations at the spatial scales represented by regional and global models. The inherent soil moisture-runoff relationships used in the LSMs are also of uncertain accuracy. Evaluating these relationships is difficult but crucial given that they have a major impact on how the land component contributes to hydrological and meteorological variability within the climate system. The relationships, it turns out, can be examined efficiently and effectively with a simple water balance model framework. The simple water balance model, driven with multi-decadal observations covering the conterminous United States, shows how different prescribed relationships lead to different manifestations of hydrological variability, some of which can be compared directly to observations. Through the testing of a wide suite of relationships, the simple model provides estimates for the underlying relationships that operate in nature and that should be operating in LSMs. We examine the relationships currently used in a number of different LSMs in the context of the simple water balance model results and make recommendations for potential first-order improvements to these LSMs.

  9. Modeling distinct imaging hemodynamics early after TBI: the relationship between signal amplitude and connectivity.

    PubMed

    Medaglia, John D; McAleavey, Andrew A; Rostami, Sohayla; Slocomb, Julia; Hillary, Frank G

    2015-06-01

    Over the past decade, fMRI studies of cognitive change following traumatic brain injury (TBI) have investigated blood oxygen level dependent (BOLD) activity during working memory (WM) performance in individuals in early and chronic phases of recovery. Recently, BOLD fMRI work has largely shifted to focus on WM and resting functional connectivity following TBI. However, fundamental questions in WM remain. Specifically, the effects of injury on the basic relationships between local and interregional functional neuroimaging signals during WM processing early following moderate to severe TBI have not been examined. This study employs a mixed effects model to examine prefrontal cortex and parietal lobe signal change during a WM task, the n-back, and whether there is covariance between regions of high amplitude signal change, (synchrony of elicited activity (SEA) very early following TBI. We also examined whether signal change and SEA differentially predict performance during WM. Overall, percent signal change in the right prefrontal cortex (rPFC) was and important predictor of both reaction time (RT) and SEA in early TBI and matched controls. Right prefrontal cortex (rPFC) percent signal change positively predicted SEA within and between persons regardless of injury status, suggesting that the link between these neurodynamic processes in WM-activated regions remains unaffected even very early after TBI. Additionally, rPFC activity was positively related to RT within and between persons in both groups. Right parietal (rPAR) activity was negatively related to RT within subjects in both groups. Thus, the local signal intensity of the rPFC in TBI appears to be a critical property of network functioning and performance in WM processing and may be a precursor to recruitment observed in chronic samples. The present results suggest that as much research moves toward large scale functional connectivity modeling, it will be essential to develop integrated models of how local and

  10. Relationship between Motivation and Learning in Physical Education and After-School Physical Activity

    ERIC Educational Resources Information Center

    Chen, Senlin; Sun, Haichun; Zhu, Xihe; Chen, Ang

    2014-01-01

    Purpose: A primary goal of physical education is to develop physically literate individuals with the knowledge, skills, and confidence necessary for a physically active lifestyle. Guided by the expectancy-value and interest motivation theories, the purpose of this study was to identify the relationship between students' motivation and…

  11. The Relationship between Students' Small Group Activities, Time Spent on Self-Study, and Achievement

    ERIC Educational Resources Information Center

    Kamp, Rachelle J. A.; Dolmans, Diana H. J. M.; van Berkel, Henk J. M.; Schmidt, Henk G.

    2012-01-01

    The purpose of this study was to investigate the relationship between the contributions students make to the problem-based tutorial group process as observed by their peers, self-study time and achievement. To that end, the Maastricht Peer Activity Rating Scale was administered to students participating in Problem-Based Learning tutorial groups.…

  12. Roles and Relationships in Student Teaching: A Role-Play Activity.

    ERIC Educational Resources Information Center

    Moses, Jeewa R.

    This role-play activity is designed for use by teacher educators in a general or content area methods class to help education majors become knowledgeable of role expectations in the student teaching experience and build good interpersonal role relationships. Students conduct library research and interviews concerning role expectations, use the…

  13. Structure-reactivity relationships between fluorescent chromophores and antioxidant activity of grain and sweet sorghum seeds

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Polyphenolic structures, such as tannins, are the putative cause of a variety of seed functions including bird/insect resistance and antioxidant activity. Structure-reactivity relationships are necessary to understand the influence of polyphenolic chromophore structures on the tannin content and fr...

  14. Physical Activity Behaviors and Emotional Self-Efficacy: Is There a Relationship for Adolescents?

    ERIC Educational Resources Information Center

    Valois, Robert F.; Umstattd, M. Renee; Zullig, Keith J.; Paxton, Raheem J.

    2008-01-01

    Background: This study explored relationships between physical activity (PA) behaviors and emotional self-efficacy (ESE) in a statewide sample of public high school adolescents in South Carolina (n = 3836). Methods: The Center for Disease Control Youth Risk Behavior Survey PA items and an adolescent ESE scale were used. Logistic regression…

  15. Sexually Active Adolescent Women: Assessing Family and Peer Relationships Using Event History Calendars

    ERIC Educational Resources Information Center

    Saftner, Melissa Ann; Martyn, Kristy Kiel; Lori, Jody Rae

    2011-01-01

    The purpose of this qualitative study is to explore family and peer relationships (including support and influence on risk behavior) among sexually active European American and African American adolescent girls in the context of risk behaviors documented on retrospective event history calendars (EHCs) and in interviews. The EHCs were completed by…

  16. The Relationship between Class Size and Online Activity Patterns in Asynchronous Computer Conferencing Environments

    ERIC Educational Resources Information Center

    Hewitt, Jim; Brett, Clare

    2007-01-01

    This study analyzes the relationship between class size and student online activity patterns in a series of 28 graduate level computer conferencing courses. Quantitative analyses of note production, average note size, note opening and note reading percentages found a significant positive correlation between class size and mean number of notes…

  17. The Relationships among Anomia, Attitude toward Adult Education, and Nonparticipation in Formal Adult Education Activities.

    ERIC Educational Resources Information Center

    Garry, Mark W.

    A study was conducted to explore the relationship between anomia (a feeling of alienation, of being cut off from society), attitude toward adult education, and nonparticipation in formal adult education activities. The subjects of the study were adults who lived in a specific area in Milwaukee, Wisconsin, which had the following characteristics:…

  18. DETERMINING THE STRUCTURE-ACTIVITY RELATIONSHIPS OF AMINOBIPHENYL AND BENZIDINE ANALOGS

    EPA Science Inventory

    Determining the structure-activity relationships of aminobiphenyl and benzidine analogues

    Benzidine is a confirmed human carcinogen causing bladder and other types of cancer in humans and animals. Many of the benzidine and related aminobiphenyl compounds are mutagenic in t...

  19. Total Synthesis and Structure-Activity Relationship of Glycoglycerolipids from Marine Organisms

    PubMed Central

    Zhang, Jun; Li, Chunxia; Yu, Guangli; Guan, Huashi

    2014-01-01

    Glycoglycerolipids occur widely in natural products, especially in the marine species. Glycoglycerolipids have been shown to possess a variety of bioactivities. This paper will review the different methodologies and strategies for the synthesis of biological glycoglycerolipids and their analogs for bioactivity assay. In addition, the bioactivities and structure-activity relationship of the glycoglycerolipids are also briefly outlined. PMID:24945415

  20. Adolescent Sexual Activity and the Development of Delinquent Behavior: The Role of Relationship Context

    ERIC Educational Resources Information Center

    Harden, K. Paige; Mendle, Jane

    2011-01-01

    Despite the well-established association between adolescent sexual activity and delinquent behavior, little research has examined the potential importance of relationship contexts in moderating this association. The current study used longitudinal, behavioral genetic data on 519 same-sex twin pairs (48.6% female) divided into two age cohorts…

  1. Relationship Between Kernel Moisture Content and Water Activity in Different Maturity Stages of Peanut

    Technology Transfer Automated Retrieval System (TEKTRAN)

    The water activity (aw) and moisture content (KMC) of individual peanut kernels representing five different maturity stages were measured during a period of late-season drought stress leading up to normal harvest time. Curves were generated describing the relationship between aw and KMC for yellow 1...

  2. The Relationship between Physical Activity Level and Healthy Life-Style Behaviors of Distance Education Students

    ERIC Educational Resources Information Center

    Özkan, Ali

    2015-01-01

    The purpose of the study was to determine the relationship between physical activity levels and healthy life-style behaviors in distance education students in Hoca Ahmet Yesevi University. In total, 526 distance education students in Hoca Ahmet Yesevi University participated in this study voluntarily. The short form of International Physical…

  3. Exploring the Relationship between Adolescent Activities and Choice of Graduate School Discipline: Implications for Creativity Development

    ERIC Educational Resources Information Center

    Hartzell, Stephanie A.; Hong, Eunsook

    2016-01-01

    The relationship between adolescent extra-curricular activities and choice of graduate-education field was examined among students from three fields of study, science (n = 12), art (n = 12), and education (n = 14), using qualitative and quantitative methods. Results of profile analysis indicated that the different majors participated in…

  4. What Are the Contributory and Compensatory Relationships between Physical Education and Physical Activity in Children?

    ERIC Educational Resources Information Center

    Morgan, Charles F.; Beighle, Aaron; Pangrazi, Robert P.

    2007-01-01

    Limited data are available on the contributory and compensatory relationships between physical education and physical activity in children. Four hundred eighty-five (280 girls) children in first through sixth grades wore sealed pedometers during waking hours, including normally scheduled physical education lessons. The least, moderately, and most…

  5. A Systematic Review of the Relationship between Socio-Economic Position and Physical Activity

    ERIC Educational Resources Information Center

    Gidlow, Christopher; Johnston, Lynne Halley; Crone, Diane; Ellis, Naomi; James, David

    2006-01-01

    Objective: The aim of the present review was to examine epidemiological evidence to determine if there is strong evidence of a positive gradient of increasing physical activity across the socio-economic strata, and how relationships are affected by socio-economic measurement. Design: Systematic review. Method: A search of major databases was…

  6. The Relationship between Students' Epistemologies and Model-Based Reasoning.

    ERIC Educational Resources Information Center

    Gobert, Janice; Discenna, Jennifer

    Models and modeling are frequently used as instructional tools in science education to convey important information concerning both the explanatory and structural features of topic areas in science. The efficacy of models as such rests almost entirely upon students' ability to conceptualize them as abstracted "representations" of scientific…

  7. Negative childhood experiences and adult love relationships: the role of internal working models of attachment.

    PubMed

    McCarthy, Gerard; Maughan, Barbara

    2010-09-01

    This study investigated links between internal working models of attachment and the quality of adult love relationships in a high risk sample of women (n = 34), all of whom reported negative parenting in childhood. Half of the sample was identified as having a history of satisfying adult love relationships, while the remainder had experienced ongoing adult relationship problems. Measures of internal working models of attachment were made using the Adult Attachment Interview (AAI). A strong association was found between attachment classifications and the quality of adult love relationships. In addition, women with satisfying love relationships demonstrated significantly higher coherence of mind ratings than those with poor relationship histories. Insecure working models of attachment were associated with problems in adult love relationships. Although secure/autonomous attachment status was linked to optimal adult relationship outcomes, some women with a history of satisfying love relationships had insecure working models of attachment. These results suggest that the ways that adults process early experiences may influence later psychosocial functioning.

  8. Daphnia and fish toxicity of (benzo)triazoles: validated QSAR models, and interspecies quantitative activity-activity modelling.

    PubMed

    Cassani, Stefano; Kovarich, Simona; Papa, Ester; Roy, Partha Pratim; van der Wal, Leon; Gramatica, Paola

    2013-08-15

    Due to their chemical properties synthetic triazoles and benzo-triazoles ((B)TAZs) are mainly distributed to the water compartments in the environment, and because of their wide use the potential effects on aquatic organisms are cause of concern. Non testing approaches like those based on quantitative structure-activity relationships (QSARs) are valuable tools to maximize the information contained in existing experimental data and predict missing information while minimizing animal testing. In the present study, externally validated QSAR models for the prediction of acute (B)TAZs toxicity in Daphnia magna and Oncorhynchus mykiss have been developed according to the principles for the validation of QSARs and their acceptability for regulatory purposes, proposed by the Organization for Economic Co-operation and Development (OECD). These models are based on theoretical molecular descriptors, and are statistically robust, externally predictive and characterized by a verifiable structural applicability domain. They have been applied to predict acute toxicity for over 300 (B)TAZs without experimental data, many of which are in the pre-registration list of the REACH regulation. Additionally, a model based on quantitative activity-activity relationships (QAAR) has been developed, which allows for interspecies extrapolation from daphnids to fish. The importance of QSAR/QAAR, especially when dealing with specific chemical classes like (B)TAZs, for screening and prioritization of pollutants under REACH, has been highlighted.

  9. [Mineralization of soil organic carbon and its relationship with soil enzyme activities in apple orchard in Weibei].

    PubMed

    Jia, Man-Li; Guo, Hong; Li, Hui-Ke

    2014-07-01

    A total of 36 kinds of soil samples were collected from apple orchards under three kinds of management model, including clear tillage model, intercropping white clover model and intercropping small crown flower model, the mineralization of soil organic carbon and four kinds of soil enzymes activities were determined, and the relationship between the two parameters was also analyzed. The results showed that the soil organic carbon mineralization of all the three treatments was almost the same. The daily SOC mineralization rate first increased and then decreased, and finally tended to be stable. After 31 days incubation experiment, the maximum accumulative amount of SOC mineralization occurred in white clover treatment with 590 mg x kg(-1), followed by small crown flower treatment with 541 mg x kg(-1), and the minimum value was 367 mg x kg(-1) in the control treatment, and the accumulative amount of SOC mineralization decreased with increasing soil depth. Discovered by the first-order kinetics, the fitting parameter Cp value ranged from 0.252 to 2.74 g x kg(-1) and k value ranged from 0.019 to 0.051 d(-1), and the two grass treatments both showed significant difference in Cp value from the control treatment, and the soil invertase and cellulose activities showed obvious relationship with soil organic carbon mineralization.

  10. [Mineralization of soil organic carbon and its relationship with soil enzyme activities in apple orchard in Weibei].

    PubMed

    Jia, Man-Li; Guo, Hong; Li, Hui-Ke

    2014-07-01

    A total of 36 kinds of soil samples were collected from apple orchards under three kinds of management model, including clear tillage model, intercropping white clover model and intercropping small crown flower model, the mineralization of soil organic carbon and four kinds of soil enzymes activities were determined, and the relationship between the two parameters was also analyzed. The results showed that the soil organic carbon mineralization of all the three treatments was almost the same. The daily SOC mineralization rate first increased and then decreased, and finally tended to be stable. After 31 days incubation experiment, the maximum accumulative amount of SOC mineralization occurred in white clover treatment with 590 mg x kg(-1), followed by small crown flower treatment with 541 mg x kg(-1), and the minimum value was 367 mg x kg(-1) in the control treatment, and the accumulative amount of SOC mineralization decreased with increasing soil depth. Discovered by the first-order kinetics, the fitting parameter Cp value ranged from 0.252 to 2.74 g x kg(-1) and k value ranged from 0.019 to 0.051 d(-1), and the two grass treatments both showed significant difference in Cp value from the control treatment, and the soil invertase and cellulose activities showed obvious relationship with soil organic carbon mineralization. PMID:25244868

  11. Harnessing structure-activity relationship to engineer a cisplatin nanoparticle for enhanced antitumor efficacy.

    PubMed

    Paraskar, Abhimanyu S; Soni, Shivani; Chin, Kenneth T; Chaudhuri, Padmaparna; Muto, Katherine W; Berkowitz, Julia; Handlogten, Michael W; Alves, Nathan J; Bilgicer, Basar; Dinulescu, Daniela M; Mashelkar, Raghunath A; Sengupta, Shiladitya

    2010-07-13

    Cisplatin is a first line chemotherapy for most types of cancer. However, its use is dose-limited due to severe nephrotoxicity. Here we report the rational engineering of a novel nanoplatinate inspired by the mechanisms underlying cisplatin bioactivation. We engineered a novel polymer, glucosamine-functionalized polyisobutylene-maleic acid, where platinum (Pt) can be complexed to the monomeric units using a monocarboxylato and an O --> Pt coordinate bond. We show that at a unique platinum to polymer ratio, this complex self-assembles into a nanoparticle, which releases cisplatin in a pH-dependent manner. The nanoparticles are rapidly internalized into the endolysosomal compartment of cancer cells, and exhibit an IC50 (4.25 +/- 0.16 microM) comparable to that of free cisplatin (3.87 +/- 0.37 microM), and superior to carboplatin (14.75 +/- 0.38 microM). The nanoparticles exhibited significantly improved antitumor efficacy in terms of tumor growth delay in breast and lung cancers and tumor regression in a K-ras(LSL/+)/Pten(fl/fl) ovarian cancer model. Furthermore, the nanoparticle treatment resulted in reduced systemic and nephrotoxicity, validated by decreased biodistribution of platinum to the kidney as quantified using inductively coupled plasma spectroscopy. Given the universal need for a better platinate, we anticipate this coupling of nanotechnology and structure-activity relationship to rationally reengineer cisplatin could have a major impact globally in the clinical treatment of cancer. PMID:20616005

  12. Predicting Cell Association of Surface-Modified Nanoparticles Using Protein Corona Structure - Activity Relationships (PCSAR).

    PubMed

    Kamath, Padmaja; Fernandez, Alberto; Giralt, Francesc; Rallo, Robert

    2015-01-01

    Nanoparticles are likely to interact in real-case application scenarios with mixtures of proteins and biomolecules that will absorb onto their surface forming the so-called protein corona. Information related to the composition of the protein corona and net cell association was collected from literature for a library of surface-modified gold and silver nanoparticles. For each protein in the corona, sequence information was extracted and used to calculate physicochemical properties and statistical descriptors. Data cleaning and preprocessing techniques including statistical analysis and feature selection methods were applied to remove highly correlated, redundant and non-significant features. A weighting technique was applied to construct specific signatures that represent the corona composition for each nanoparticle. Using this basic set of protein descriptors, a new Protein Corona Structure-Activity Relationship (PCSAR) that relates net cell association with the physicochemical descriptors of the proteins that form the corona was developed and validated. The features that resulted from the feature selection were in line with already published literature, and the computational model constructed on these features had a good accuracy (R(2)LOO=0.76 and R(2)LMO(25%)=0.72) and stability, with the advantage that the fingerprints based on physicochemical descriptors were independent of the specific proteins that form the corona.

  13. Quantitative structure-activity relationships for weak acid respiratory uncouplers to Vibrio fisheri

    SciTech Connect

    Schultz, T.W.; Cronin, M.T.D.

    1997-02-01

    Acute toxicity values of 16 organic compounds thought to elicit their response via the weak acid respiratory uncoupling mechanism of toxic action were secured from the literature. Regression analysis of toxicities revealed that a measured 5-min V. fisheri potency value can be used as a surrogate for the 30-min value. Regression analysis of toxicity versus hydrophobicity, measured as the 1-octanol/water partition coefficient (log K{sub ow}), was used to formulate a quantitative structure-activity relationship (QSAR). The equation log pT{sub 30}{sup {minus}1} = 0.489(log K{sub ow}) + 0.126 was found to be a highly predictive model. This V. fisheri QSAR is statistically similar to QSARs generated from weak acid uncoupler potency data for Pimephales promelas survivability and Tetrahymena pyriformis population growth impairment. This work, therefore, suggests that the weak acid respiratory uncoupling mechanism of toxic action is present in V. fisheri, and as such is not restricted to mitochondria-containing organisms.

  14. Representation of molecular structure using quantum topology with inductive logic programming in structure-activity relationships.

    PubMed

    Buttingsrud, Bård; Ryeng, Einar; King, Ross D; Alsberg, Bjørn K

    2006-06-01

    The requirement of aligning each individual molecule in a data set severely limits the type of molecules which can be analysed with traditional structure activity relationship (SAR) methods. A method which solves this problem by using relations between objects is inductive logic programming (ILP). Another advantage of this methodology is its ability to include background knowledge as 1st-order logic. However, previous molecular ILP representations have not been effective in describing the electronic structure of molecules. We present a more unified and comprehensive representation based on Richard Bader's quantum topological atoms in molecules (AIM) theory where critical points in the electron density are connected through a network. AIM theory provides a wealth of chemical information about individual atoms and their bond connections enabling a more flexible and chemically relevant representation. To obtain even more relevant rules with higher coverage, we apply manual postprocessing and interpretation of ILP rules. We have tested the usefulness of the new representation in SAR modelling on classifying compounds of low/high mutagenicity and on a set of factor Xa inhibitors of high and low affinity.

  15. The Exploration of the Relationship between Guessing and Latent Ability in IRT Models

    ERIC Educational Resources Information Center

    Gao, Song

    2011-01-01

    This study explored the relationship between successful guessing and latent ability in IRT models. A new IRT model was developed with a guessing function integrating probability of guessing an item correctly with the examinee's ability and the item parameters. The conventional 3PL IRT model was compared with the new 2PL-Guessing model on…

  16. [A clinical study on the relationship between chewing movements and masticatory muscle activities].

    PubMed

    Higashi, K

    1989-06-01

    Chewing movement is one of the most important functional and physiological jaw movements, and it is coordinated by the three elements of the functional occlusion system (teeth, TMJs and masticatory muscles). However, the relationship between chewing movement and these elements has not been clarified. The purpose of this study was to investigate the relationship between chewing movement and the activity of the masticatory muscles which directly control jaw movements. 25 subjects with normal stomatognathic function, 5 patients with MPD syndrome (muscle dysfunction group) and 5 patients with unilateral TMJ internal derangement (TMJ dysfunction group) were selected. 6 gums with different hardness were used as the test bolus. Sirognathograph Electromyograph Analysing System was used to simultaneously record chewing movements and electromyograms of the right and left masseter, anterior temporal, posterior temporal and anterior belly of digastric muscles. Using the analysing software which was developed for this study, chewing movements and muscle activities were analysed. The results were as follow; A. In normal subjects 1. Gum hardness influenced durations of the closing and occluding phases, maximum opening and closing speed, opening degree and deviation of opening and closing path. 2. Gum hardness influenced muscle activities except of the time factors of digastric bursts. 3. Durations of the closing and occluding phases were found to be related with the elevator muscle activities. Maximum closing speed was related with the masseter and anterior temporal muscle activities. Deviation of closing path was related with the anterior and posterior temporal muscle activities. B. In abnormal subjects 1. The changes mainly observed in the muscle activities were found to be significantly different between the muscle dysfunction group and normal group. Similarly, the changes mainly observed in the chewing movements were different between the TMJ dysfunction group and normal

  17. Modeling the relationship between the environment and human experiences.

    PubMed

    Vink, P; Bazley, C; Jacobs, K

    2016-08-12

    Within this special issue, different aspects of the environment are studied: aspects that are distant from the human body, close to the body and touching the human body. Consequently, different human senses are involved in these studies as well as the different consequences and effects on the brain and human behaviour. This special issue also highlights many remaining questions about the effects and relationships between environments and human beings and the need for more studies and research. In particular, future studies are needed that address long-term effects and the effects of the combinations of elements which provide comfort or discomfort.

  18. Modeling the relationship between the environment and human experiences.

    PubMed

    Vink, P; Bazley, C; Jacobs, K

    2016-08-12

    Within this special issue, different aspects of the environment are studied: aspects that are distant from the human body, close to the body and touching the human body. Consequently, different human senses are involved in these studies as well as the different consequences and effects on the brain and human behaviour. This special issue also highlights many remaining questions about the effects and relationships between environments and human beings and the need for more studies and research. In particular, future studies are needed that address long-term effects and the effects of the combinations of elements which provide comfort or discomfort. PMID:27567796

  19. Energy-Based Pharmacophore and Three-Dimensional Quantitative Structure--Activity Relationship (3D-QSAR) Modeling Combined with Virtual Screening To Identify Novel Small-Molecule Inhibitors of Silent Mating-Type Information Regulation 2 Homologue 1 (SIRT1).

    PubMed

    Pulla, Venkat Koushik; Sriram, Dinavahi Saketh; Viswanadha, Srikant; Sriram, Dharmarajan; Yogeeswari, Perumal

    2016-01-25

    Silent mating-type information regulation 2 homologue 1 (SIRT1), being the homologous enzyme of silent information regulator-2 gene in yeast, has multifaceted functions. It deacetylates a wide range of histone and nonhistone proteins; hence, it has good therapeutic importance. SIRT1 was believed to be overexpressed in many cancers (prostate, colon) and inflammatory disorders (rheumatoid arthritis). Hence, designing inhibitors against SIRT1 could be considered valuable. Both structure-based and ligand-based drug design strategies were employed to design novel inhibitors utilizing high-throughput virtual screening of chemical databases. An energy-based pharmacophore was generated using the crystal structure of SIRT1 bound with a small molecule inhibitor and compared with a ligand-based pharmacophore model that showed four similar features. A three-dimensional quantitative structure-activity relationship (3D-QSAR) model was developed and validated to be employed in the virtual screening protocol. Among the designed compounds, Lead 17 emerged as a promising SIRT1 inhibitor with IC50 of 4.34 μM and, at nanomolar concentration (360 nM), attenuated the proliferation of prostate cancer cells (LnCAP). In addition, Lead 17 significantly reduced production of reactive oxygen species, thereby reducing pro inflammatory cytokines such as IL6 and TNF-α. Furthermore, the anti-inflammatory potential of the compound was ascertained using an animal paw inflammation model induced by carrageenan. Thus, the identified SIRT1 inhibitors could be considered as potent leads to treat both cancer and inflammation.

  20. Energy-Based Pharmacophore and Three-Dimensional Quantitative Structure--Activity Relationship (3D-QSAR) Modeling Combined with Virtual Screening To Identify Novel Small-Molecule Inhibitors of Silent Mating-Type Information Regulation 2 Homologue 1 (SIRT1).

    PubMed

    Pulla, Venkat Koushik; Sriram, Dinavahi Saketh; Viswanadha, Srikant; Sriram, Dharmarajan; Yogeeswari, Perumal

    2016-01-25

    Silent mating-type information regulation 2 homologue 1 (SIRT1), being the homologous enzyme of silent information regulator-2 gene in yeast, has multifaceted functions. It deacetylates a wide range of histone and nonhistone proteins; hence, it has good therapeutic importance. SIRT1 was believed to be overexpressed in many cancers (prostate, colon) and inflammatory disorders (rheumatoid arthritis). Hence, designing inhibitors against SIRT1 could be considered valuable. Both structure-based and ligand-based drug design strategies were employed to design novel inhibitors utilizing high-throughput virtual screening of chemical databases. An energy-based pharmacophore was generated using the crystal structure of SIRT1 bound with a small molecule inhibitor and compared with a ligand-based pharmacophore model that showed four similar features. A three-dimensional quantitative structure-activity relationship (3D-QSAR) model was developed and validated to be employed in the virtual screening protocol. Among the designed compounds, Lead 17 emerged as a promising SIRT1 inhibitor with IC50 of 4.34 μM and, at nanomolar concentration (360 nM), attenuated the proliferation of prostate cancer cells (LnCAP). In addition, Lead 17 significantly reduced production of reactive oxygen species, thereby reducing pro inflammatory cytokines such as IL6 and TNF-α. Furthermore, the anti-inflammatory potential of the compound was ascertained using an animal paw inflammation model induced by carrageenan. Thus, the identified SIRT1 inhibitors could be considered as potent leads to treat both cancer and inflammation. PMID:26636371